CDK inhibitors having flavone structure

ABSTRACT

The present invention relates to a novel flavone derivative, pharmaceutically acceptable salt, hydrate, solvate and isomer thereof which is useful as an inhibitor against Cyclin Dependent Kinase (CDK), a process for preparation thereof, and a composition of anti-cancer agent or agent for treating neurodegenerative disease comprising this compound as an active ingredient.

This application is a 371 of PCT/KR99/00499 Aug. 31, 1999.

TECHNICAL FIELD

The present invention relates to a novel flavone derivative representedby the following formula (1):

in which

R₁, R₃ and R₄ each independently represent hydrogen, halogen, hydroxy,alkyl, lower alkoxy, amino or nitro,

R₂ represents hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy,amino, nitro or

 wherein

A represents amino which may be optionally substituted with alkyl,cycloalkyl, aralkyl, acyl, or aryl which is optionally substituted withone or two substituents selected from the group consisting of halogen,cyano, nitro and amino; or 1,2,3,4-tetrahydroisoquinoline which may beoptionally substituted with halogenoalkylcarbonyl; or alkyl, aryl,aralkyl or heteroaryl each of which may be optionally substituted withone or two substituents selected from the group consisting of alkyl,halogenoalkyl, halogen, dialkylamino, phenyl, nitro, amino, isooxazole,pyridine, carboxy, morpholine, methylpiperazine and cyano,

Y represents SO₂ or CO,

B represents hydrogen or alkyl,

R₅ represents hydrogen or hydroxy, and

R₆ and R₇ are substituted at o-, m- or p-position from each other andeach independently represents hydrogen, hydroxy, halogen or lower alkoxyor together represent lower alkylenedioxy,

pharmaceutically acceptable salt, hydrate, solvate and isomer thereofwhich is useful as an inhibitor for Cyclin Dependent Kinase(hereinafter, referred to as “CDK”),

In addition, the present invention relates to a process for preparingthe flavone derivative of formula (1) and also relates to an anti-canceragent or an agent for treating neurodegenerative disease characterizedby comprising the compound of formula (1) as an active ingredient.

BACKGROUND ART

Researches on cell division process in molecular level have beenextensively performed from the late 1980's through study of division offrog oocytes, analysis several yeast cell growth or characterization ofinduced mutants by radiation and study of the tumor suppressor Rb. Inthe 1990's, it is discovered that small molecular cell growth regulatorcontrols cell division process (i.e. growth, differentiation,cytogenesis, aging and apoptosis etc.) through its own regulatoryfunction. These results were very useful for more precise understandingof the pathology of several diseases.

A representative example is cancer. In transformation process fromnormal cells to cancer cells, it was frequently observed that cellgrowth regulator loses its own function. That is to say, in cancercells, the cell growth regulator shows an abnormal activity, which isdeeply associated with invasion/metastasis which is crucial in thecancerpathology. Particularly, cell cycle deregulation is recognized tobe a direct cause of cancer since cancer occurs in experimental animalwhen overexpression or knock-out of cell growth regulator is induced byusing tranformed animal.

The cell growth is under positive or negative regulation in the samemanner as other biological regulations. The major pathway of cell cycleregulation known up to now is based on CDK activity and as a result ofstudies on many cancer cells and carcinogenesis mechanisms, it wasconfirmed that problems of positive or negative regulation on CDKactivity result in carcinogenesis in many cases. That is, cancer mayoccur when positive or negative regulation and timely regulation whichis important for cell growth regulation are disrupted.

The representative CDKs of mammals are CDK4 (Cyclin dependent kinase 4)which shows its activity in mid-G1 phase of cell cycle, CDK2 which showsits activity in mid-1 and S phases, CDC2 (CDK1) which shows its activityin G2-M phase, and so on. It is known that CDK4 and CDK2 activities areregulated by check point of G1-S cell cycle and CDC2 activity by checkpoint of G2-M. In many cancer cells, abnormalities appear in theregulatory mechanism of CDK4, CDK2 and CDC2 (CDK 1) and in fact, it wasconfirmed that induced abnormalities cause cancer in the transformedanimal. Therefore, CDK4, CDK2 and CDC2 (CDK1) among several kinds ofCDKs are suitable as a target of anti-cancer agents.

The results of studies on relation between these CDKs andcarcinogtenesis will be explained in more detail in the following.

The relation between the abnormal regulation of CDK4 activity andcarcinogenesis is observed in several cancer tissues. The deletion ofp16 and p15 genes in several kinds of cancer is reported andparticularly, overexpression of cyclin D1 is observed, which has closerelation with the fact that breast cancer has a metastatic proper andwhich suggests that malignant phenotype may be expressed when CDK4activity is deregulated.

Furthermore, it was reported that p16 knocked-out mouse has such a highcarcinogenesis rate as p53 knocked-out mouse, which suggests thatmalfunction of p16 on CDK4 regulation is a cause of carcinogenesis. Itgives the possibility that p16 plays a role in the downstream in NIH 3T3cell with overexpressed ras or src. Reversely it was observed thatmodified phenotype wherein p16 or p21 is transformed with ras isrepaired into wild phenotype. From these experimental results,deregulation of CDK4 activity may be a cause of carcinogenesis and playa role in maintenance of phenotype of cancer cell. Therefore, CDK4inhibitors may have anti-cancer effects.

It was reported that overexpression of cyclin E is observed in somebreast cancers, deeply associated with metastasis of breast cancer,inhibits cell apoptosis under low serum condition and induces anchorageindependent growth, and that hyperproliferation (neoplasia) of mammaryepithelial cells is observed in transformed animal with overexpressedCDK2 by MMTV promoter, which suggests that CDK2 activity is related withthe progress or maintenance of cell transformation and CDK2 inhibitorsmay also have anti-cancer effects.

It is recently discovered that CDK5 among these CDKs may causeneurodegenerative diseases by phosphorylation of tau protein of thebrain. Therefore, CDK5 inhibitor may be useful as an agent for treatingneurodegenerative diseases (e.g. Alzheimer's disease). CDK2 inhibitorsmay have inhibitory effects on CDK5 in that CDK2 and CDK5 are homologousin the same family (Ref.: John Leu et al., “Neuronal CDC2-like kinase”,TIBS, January 1995, pp33˜37).

Furthermore, it is discovered that CDC2 (CDK1), CDK3, CDK6 and CDK7 playan important role in each phase of cell division. These are classifiedinto CDKs family. In addition, to cyclin D1 and E, cyclin A, B, C, D2,D3, D4, F and G are also calssified into the same family.

On the basis of the above-mentioned research, efficient inhibitors ofthese CDKs may be useful as anti-cancer or anti-neurodegenerativeagents. Therefore, recently, these inhibitors have been developed.

As effective CDK inhibitors developed hitherto, there existsFlavopiridol, compound of the formula (2)

which is under clincal trials [Ref.: EP 0,241,003 and 0,336,061]. Inaddition, a purine derivative of the formula (3)

has been recently developed [Ref: WO 97/16447].

However, the CDK inhibitors developed up to now could not havesatisfactory effects.

So, the present inventors have made widespread and concentrativeresearches on CDK inhibitors and as a result, found that the aboveflavone derivative of formula (1) which has a quite different structurefrom any other known CDK inhibitors inhibits CDKs effectively andfinally. complete the present invention.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide a novel flavonederivative of formula (1), pharmaceutically acceptable salt, hydrate,solvate and isomer thereof having an inhibitory activity for CDK.

Another object of the present invention is to provide a process forpreparing the compound of formula (1). Still another object of thepresent invention is to provide an anti-cancer agent and an agent fortreating neurodegenerative disease each of which is characterized bycomprising as an active ingredient the compound of formula (1) with apharmaceutically acceptable carrier.

In this specification, CDKs includes all of CDK2, CDK4, CDC2 (CDK1),CDK3, CDK5, CDK6, CDK7 etc., and cyclin includes cyclin D1, E, A, B, C,D2, D3, D4, F, and G.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained in detail hereinafter.

The present invention relates to a novel flavone derivative representedby the following formula (1):

in which

R₁, R₃ and R₄ each independently represent hydrogen, halogen. hydroxy,alkyl, lower alkoxy, amino or nitro.

R₂ represents hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy,amino, nitro or

 wherein

A represents amino which may be optionally substituted with alkyl,cycloalkyl, aralkyl, acyl, or aryl which is optionally substituted withone or two substituents selected from the group consisting of halogen,cyano, nitro and amino; or 1,2,3,4-tetrahydroisoquinoline which may beoptionally substituted with halogenoalkylcarbonyl; or alkyl, aryl,aralkyl or heteroaryl each of which may be optionally substituted withone or two substituents selected from the group consisting of alkyl,halogenoalkyl, halogen, dialkylamino, phenyl, nitro, amino, isooxazole,pyridine, carboxy, morpholine, methylpiperazine and cyano,

Y represents SO₂ or CO,

B represents hydrogen or alkyl,

R₅ represents hydrogen or hydroxy, and

R₆ and R₇ are substituted at o-, m- or p-position from each other andeach independently represents hydrogen, hydroxy, halogen or lower alkoxyor together represent lower alkylenedioxy,

pharmaceutically acceptable salt, hydrate, solvate and isomer thereofwhich has efficacies on treating cancer or neurodegenerative diseasethrough a mechanism of inhibiting CDKs activity,

In addition, the present invention relates to a process for preparingthe flavone derivative of formula (1) and also relates to an anti-canceragent or an agent for treating neurodegenerative disease each of whichis characterized by comprising the compound of formula (1) as an activeingredient.

Among the compound of formula (1) according to the present invention,the preferred compounds include those wherein

(1) R₁, R₂, R₃ and R₄ each independently represent hydrogen, halogen.hydroxy, lower alkoxy or nitro (provided that two or more of these foursubstituents are hydrogen),

R₅ represents hydrogen or hydroxy, and

R₆ and R₇ are substituted at o-, m- or p-position from each other andeach independently represents hydrogen, hydroxy, halogen or lower alkoxyor together represent lower alkylenedioxy, or

(2) R₁ represents hydrogen, hydroxy, lower alkoxy or amino,

R₂ and R₃ each independently represent hydrogen, halogen, hydroxy, loweralkyl, lower alkoxy or amino,

R₄ represents hydrogen, halogen, hydroxy or lower alkoxy,

R₅ represents hydroxy, and

R₆ and R₇ represent 3-hydroxy and 4-hydroxy respectively, or

(3) R₁, R₃ and R₄ each independently represent hydrogen, halogen,hydroxy, alkyl or amino (provided that two or more of these threesubstituents are hydrogen),

R₂ represents

 wherein

A represents amino which may be optionally substituted with alkyl,cycloalkyl, aralkyl, acyl, or amyl which is optionally substituted withone or two substituents selected from the group consisting of halogen,cyano, nitro and amino; or 1,2,3,4-tetrahydroisoquinoline which may beoptionally substituted with halogenoalkylcarbonyl; or alkyl, aryl,aralkyl or heteroaryl each of which may be optionally substituted withone or two substituents selected from the group consisting of alkyl,halogenoalkyl, halogen, dialkylamino, phenyl, nitro, amino, isooxazole,pyridine, carboxy, morpholine, methylpiperazine and cyano,

Y represents SO₂ or CO,

B represents hydrogen or alkyl,

R₅ represents hydroxy, and

R₆ and R₇ represent 3-hydroxy and 4-hydroxy respectively.

More preferred compounds include those wherein

(1) R₁, R₂, R₃ and R₄ each independently represent hydrogen, chloro,hydroxy, methoxy or nitro(provided that two or more of these foursubstituents are hydrogen),

R₅ represents hydrogen or hydroxy, and

R₆ and R₇ are substituted at o-, m- or p-position from each other andeach independently represents hydrogen, hydroxy, chloro or methoxy ortogether represent methylenedioxy, or

(2) R₁ represents hydrogen, hydroxy or lower alkoxy,

R₂ represents hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy oramino,

R₃ represents hydrogen, hydroxy, lower alkyl, lower alkoxy or amino,

R₄ represents hydrogen, halogen or hydroxy,

R₅ represents hydroxy, and

R₆, and R₇ represent 3-hydroxy and 4-hydroxy respectively, or

(3) R₁, R₃ and R₄ each represent hydrogen,

R₂ represents

 wherein

A represents amino which may be optionally substituted with cycloalkyl;or 1,2,3,4-tetrahydroisoquinoline which may be optionally substitutedwith halogenoalkylcarbonyl; or alkyl, aryl, aralkyl or heteroaryl eachof which may be optionally substituted with one or two substituentsselected from the group consisting of alkyl, halogenoalkyl, halogen,dialkylamino, phenyl. nitro, amino isooxazole, pyridine carboxy,morpholine and methylpiperazine,

Y represents SO₂,

B represents hydrogen,

R₅ represents hydroxy, and

R₆ and R₇ represent 3-hydroxy and 4-hydroxy respectively, or

(4) R₁, R₃ and R₄ each represent hydrogen

R₂ represents

 wherein

A represents amino which may be optionally substituted with cycloalkyl,aralkyl, acyl, or aryl which is optionally substituted with one or twosubstituents selected from the group consisting of halogen, cyano, nitroand amino; or alkyl or aryl each of which may be optionally substitutedwith halogen,

Y represents CO,

B represents hydrogen,

R₅ represents hydroxy, and

R₆ and R₇ represent 3-hydroxy and 4-hydroxy respectively.

Most preferred compounds include those wherein

(1) R₁ represents hydrogen, hydroxy or methoxy,

R₂ represents hydrogen, bromine, hydroxy, methyl or amino,

R₃ represents hydrogen, hydroxy, methyl, methoxy or amino,

R₄ represents hydrogen, halogen or hydroxy,

R₅ represents hydroxy, and

R₆ and R₇ represent 3-hydroxy and 4-hydroxy respectively, or

(2) R₁, R₃ and R₄ each represent hydrogen,

R₂ represents

 wherein

A represents 1,2,3,4-tetrahydroisoquinoline which may be optionallysubstituted with halogenoalkylcarbonyl or aryl or heteroaryl each ofwhich may be optionally substituted with one or two substituentsselected from the group consisting of alkyl, halogenoalkyl, halogen,dialkylamino, phenyl, nitro, amino, isooxazole, pyridine, carboxy,morpholine and methylpiperazine,

Y represents SO₂,

B represents hydrogen,

R₅ represents hydroxy, and

R₆ and R₇ represent 3-hydroxy and 4-hydroxy respectively, or

(3) R₁, R₃ and R₄ each represent hydrogen,

R₂ represents

 wherein

A represents amino which is substituted with aryl which is substitutedwith one or two substituents selected from the group consisting ofhalogen, cyano, nitro and amino,

Y represents CO,

B represents hydrogen,

R₅ represents hydroxy, and

R₆ and R₇ represent 3-hydroxy and 4-hydroxy respectively.

Typical examples of the flavone derivative of formula (1) according tothe present invention are

compound 1) 2-(4-chloro-phenyl)-7-methoxy-chromen-4-one,

compound 2) 7-methoxy-2-phenyl-chromen-4-one,

compound 3) 7-hydroxy-2-phenyl-chromen-4-one.

compound 4) 2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-5-methoxy-chromen-4-one,

compound 5) 2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-6-methoxy-chromen-4-one,

compound 6) 2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-7-methoxy-chromen-4-one,

compound 7) 3-hydroxy-7-methoxy-2-(4-methoxy-phenyl)-chromen-4-one,

compound 8) 2-(4-chloro-phenyl)-3-hydroxy-7-methoxy-chromen-4-one,

compound 9)6-chloro-3-hydroxy-2-(4-methoxy-phenyl)-8-nitro-chromen-4-one,

compound 10) 6,8-dichloro-3-hydroxy-2-(4-methoxy-phenyl)-chromen-4-one,

compound 11) 3-hydroxy-2-(4-methoxy-phenyl)-chromen-4-one,

compound 12)6-chloro-2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-4-one,

compound 13) 6-bromo-2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-4-one,

compound 14) 2-(3,4-dihydroxyphenyl)-3,6-dihydroxy-4H-chromen-4-one,

compound 15) 6-amino-2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-4-one,

compound 16)2-(3,4-dihydroxyphenyl)-3-hydroxy-6-methoxy-4H-chromen-4-one,

compound 17)6-fluoro-2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-4-one,

compound 18)6-methyl-2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-4-one,

compound 19)6,8-dichloro-2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-4-one,

compound 20)6,8-dibromo-2-(3,4-dihydoxyphenyl)-3-hydroxy-4H-chromen-4-one,

compound21)6,8-difluoro-2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-4-one,

compound 22)6-chloro-2-(3,4-dihydroxyphenyl)-3-hydroxy-7-methyl-4H-chromen4-one,

compound 23)2-(3,4-dihydroxyphenyl)-3-hydroxy-7-methoxy4H-chromen-4-one,

compound 24)2-(3,4-dihydroxyphenyl)-3,8-dihydroxy-7-methoxy-4H-chromen-4-one,

compound 25) 2-(3,4-dihydroxyphenyl)-3,8-dihydroxy-4H-chromen-4-one,

compound 26)2-(3,4-dihydroxyphenyl)-6,7-dimethyl-3-hydroxy-4H-chromen-4-one,

compound 27)2-(3,4-dihydroxyphenyl)-3-hydroxy-5-methoxy-4H-chromen-4-one,

compound 28)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-methylbenzenesulfonamide,

compound 29)4-bromo-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]benzenesulfonamide,

compound 30)3-bromo-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]benzenesulfonamide,

compound 31)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2-naphthalenesulfonamide,

compound 32)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-5-(dimethylamino)-1-naphthalenesulfonamide,

compound 33)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2-(1-naphthyl)-1-ethanesulfonamide,

compound 34)4,5-dibromo-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-41-1-chromen-6-yl]-2-thiophenesulfonamide,

compound 35)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-[1,1′-diphenyl]-4-sulfonamide,

compound 36)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-5-(isooxazolyl)-2-thiophenesulfonamide,

compound 37)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-5-(2-pyridinyl)-2-thiophenesulfonamide,

compound 38)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-3,4-difluorobenzenesulfonamide,

compound 39)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(trifluoromethyl)benzenesulfonamide,

compound 40)4-chloro-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-3-nitrobenzenesulfonamide,

compound 41)3-chloro-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-1-propanesulfonamide,

compound 42)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2,4-difluorobenzenesulfonamide,

compound 43)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-fluorobenzenesulfonamide,

compound 44)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinesulfonamide,

compound 45)4-({[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]amino}sulfonyl)benzoicacid,

compound 46)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-1,2,3,4-tetrahydro-7-isoquinolinesulfonamide,

compound 47)N-cyclohexyl-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-sulfide,

compound 48)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(4-morpholinyl)-3-nitrobenzenesulfonamide,

compound 49)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamide,

compound 50)3-amino-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(4-methyl-1-piperazinyl)benzenesulfonamide,

compound 51)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]acetamide,

compound 52)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]benzamide,

compound 53)4-chloro-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]benzamide,

compound 54)N-benzyl-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]urea,

compound 55)N-(4-bromophenyl)-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]urea,

compound 56)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-N′-phenylurea,

compound 57)N-benzoyl-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]urea,

compound 58)N-(3-bromophenyl)-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]urea,

compound 59)N-(2,4-dichlorophenyl)-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-urea,

compound 60)N-(3-cyanophenyl)-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]urea,

compound 61)N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-N′-(4-nitrophenyl)urea,

compound 62)N-(4-aminophenyl)-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]urea,

compound 63) 2-(3,4-dihydroxyphenyl)-3-hydoxy-4H-chromen-4-one,

compound 64) 2-(3,4-dihydroxyphenyl)-3,7-dihydroxy-4H-chromen-4-one,

compound 65) 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one,and

compound 66) 2-(3,4-dihydroxyphenyl)-3,7,8-trihydroxy-4H-chromen-4-one.

The above compound of formula (1) may also form a pharmaceuticallyacceptable salt. Such a salt includes non-toxic acid addition saltcontaining pharmaceutical acceptable anion, for example a salt withinorganic acids such as hydrochloric acid, sulfuric acid, nitric acid,phosphoric acid, hydrobromic acid, hydroiodic acid, etc., a salt withorganic carboxylic acids such as tartaric acid, formic acid, citricacid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconicacid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., or asalt with sulfonic acids such as methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc. Thecompound of formula (1) may also exist in the form of hydrate orsolvate.

Since the compounds according to the present invention may haveasymmetric carbon centers, they can be present in the form of racemate,diastereomer or mixtures thereof. Therefore, the present invention alsoincludes all these isomers and their mixtures.

The compound of the formula (1) according to the present invention maybe prepared by process described in the following.

First, the compound of formula (1) wherein R₅ is hydrogen, namely thecompound of the following formula (1a):

wherein R₁, R₂, R₃, R₄; and R₇ are defined as previously described, or asalt thereof may be prepared characterized by

a) cyclizing a compound of the following formula (4):

wherein R₁, R₂, R₃, R₄, R₆ and R₇ are defined as previously described,in the presence of trifluoroacetic acid to give a compound of thefollowing formula (5):

wherein R₁, R₂, R₃, R₄, R₆ and R₇ are defined as previously described,then reducing the resulting compound of formula (5) in the presence of areducing agent in a solvent or

b) cyclizing a compound of the following formula (6):

wherein R₁, R₂, R₃, R₄, R₆ and R₇ are defined as previously described,in the presence of sodium acetate in a solvent.

The processes are depicted in the following Schemes (1) and (2).

wherein R₁, R₂, R₃, R₄, R₆ and R₇ are defined as previously described.

In the reaction depicted in Scheme (1), the compound of formula (5) isprepared from cyclization of the compound of formula (4) during whichthe compound (4) is heated under reflux in the presence oftrifluoroacetic acid. This reaction is carried out for an enough time,usually for a day, to complete the reaction depending on the kind ofreactant. After the cyclization is completed, the chromane derivative offormula (5) thus obtained is oxidized with a oxidizing agent in asolvent to produce the chromene derivative of above formula (1a). As thesolvent, one or more selected from the group consisting of benzene andtoluene may be preferably used. As the oxidizing agent,2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is used preferably.

In the reaction according to Scheme (2). the compound of formula (1a)wherein R₅ is hydrogen is prepared by cyclizing the compound of formula(6) in the presence of sodium acetate in a solvent. At this time, aceticacid is preferably used as the solvent.

Second, the compound of formula (1) wherein R₅ is hydroxy, namely thecompound of following formula (1b):

wherein R₁, R₂, R₃, R₄, R₆ and R₇ are defined as previously described,or a salt thereof may be prepared characterized by cyclizing thecompound of following formula (4):

wherein R₁, R₂, R₃, R₄, R₆ and R₇ are defined as previously described,in the presence of a base and hydrogen peroxide in a solvent.

Especially, the compound of formula (1b) wherein R₆ and R₇ togetherrepresent methylenedioxy, namely the compound of formula (1cc):

wherein R₁, R₂, R₃ and R₄ are defined as previously described, can beprepared from the compound of following formula (4a):

wherein R₁, R₂, R₃ and R₄ are defined as previously described, accordingto the above method.

The process of the above reaction is depicted in the following Scheme(3).

wherein R₁, R₂, R₃, R₄, R₆ and R₇ are defined as previously described.

In the reaction according to the Scheme (3), the compound of formula(1b) is prepared by cyclizing compound of formula (4) in the presence ofhydrogen peroxide. In this process, a solvent and a base are used. Asthe solvent, the one which does not adversely affect the reaction, suchas for example, one or more selected from the group consisting ofmethanol and ethanol, particularly methanol is used. The base includesone or more selected from the group consisting of sodium hydroxide andpotassium hydroxide. Particularly an aqueous sodium hydroxide solutionhaving a concentration of 10% is preferable. This reaction should beconducted inevitably by using hydrogen peroxide which is used in excessamount, preferably in an amount of 5 to 10 times molar equivalents withrespect to the compound of formula (4). Suitably, it is used in anaqueous solution of 30%. The reaction may be promoted by optionallyadding acid catalyst, such as hydrochloric acid. The reaction is usuallycarried out at room temperature or under warming, and about 3 hours areusually required to complete the reaction at room temperature.

Deprotection reaction may also be carried out to remove the amino- orhydroxy-protecting group which exists optionally.

That is to say, the compound of formula (1) wherein one or more of thesubstituents R₁, R₂, R₃ and R₄ are hydroxy or amino may be preparedcharacterized by selectively deprotecting the hydroxy or amino groupwhich is protected by lower alkyl or alkanoyl in the presence of borontribromide or by hydrolyzing with aqueous sulfuric acid solution oralcohol solvent.

Moreover, the compound of formula (1) wherein R₂ is

namely the compound of the following formula (1h):

wherein R₁, R₃, R₄, R₅ and A, Y, B are defined as previously described,may be prepared by reacting the compound of formula (9):

wherein R₁, R₃, R₄, R₅ and B are defined as previously described, withthe compound of formula (10):

A—Y—X  (10)

wherein A and Y are defined as previously described and X is a leavinggroup, or with the compound of formula (11):

A′—N═C═O  (11)

wherein A′ represents aralkyl, acyl or aryl which is optionallysubstituted with one or two substituents selected from the groupconsisting of halogen, cyano and nitro.

Especially, the compound of formula (1h) wherein R₅ is hydroxy, namelythe compound of formula (1hh):

wherein R₁, R₃, R₄, A, Y and B are defined as previously described, canbe prepared from the compound of formula (9a):

wherein R₁, R₃, R₁and B are defined as previously described, accordingto the above method.

The compound of formula (9), especially the compound of formula (9a)used in the above method can be prepared by process described in thefollowing.

A compound of formula (4b):

wherein R₁, R₃, R₄ and B are defined as previously described, isprepared by reacting 2-hydroxyacetophenone derivative of formula (7a):

wherein R₁, R₃, R₄ and B are defined as previously described, thepiperonal of formula (8a):

and sodium hydroxide in the aqueous ethanol solution solvent, then thusobtained compound of formula (4b) is reacted with aqueous sodiumhydroxide and hydrogen peroxide in methanol solvent to produce acompound of formula (1e):

wherein R₁, R₃, R₄ and B are defined as previously described.

Then, the above obtained compound of formula (1e) is hydrolyzed withaqueous sulfuric acid solution in alcoholic solvent to give a compoundof formula (9a):

wherein R₁, R₃, R₄ and B are defined as previously described.

The compound of formula (1) wherein one to six of the substituents R₁,R₂, R₃, R₄, R₆ and R₇ are hydroxy may be prepared characterized byselectively deprotecting one to six lower alkoxy groups or loweralkylenedioxy group in the compound of formula (1) in order to convertthem into hydroxy of dihydroxy group in the presence of borontribromide.

For example, the compound of formula (1) wherein R₆ and R₇ represent3-hydroxy and 4-hydroxy respectively, namely compound of formula (1d):

wherein R₁, R₂, R₃, R., and R₅ are defined as previously described, maybe prepared from the compound of formula (1c):

wherein R₁, R₂, R₄, R₄, and R₅ are defined as previously described,according to the reaction as depicted in the following Scheme (4).

wherein R₁, R₂, R₃, R₄, and R₅ are defined as previously described.

Especially, the compound formula (1d) wherein R₅ is hydroxy, namely thecompound of formula (1dd):

wherein R₁, R₂, R₃ and R₄ are defined as previously described, can beprepared from the compound of formula (1cc):

wherein R₁, R₂, R₃ and R₄ are defined as previously described, accordingto the above method.

In addition, the compound of formula (1cc) wherein R₂ is

namely the compound of formula (1i):

wherein R₁, R₃, R₄, A, Y and B are defined as previously described, canbe prepared from the compound of formula (1hh):

wherein R₁, R₃, R₄, A, Y and B are defined as previously described,according to the above method.

In the reaction according to Scheme 4, the compound of formula (1d) isprepared by opening the dioxolane ring of the compound of formula (1c)to convert it into dihydroxy group. The opening of dioxolane ring isaccomplished by a reaction with boron tribromide which is usually usedin an amount of 2 to 5 equivalents, preferably 3 equivalents or more,with respect to the compound of formula (1c). This opening reaction ispreferably carried out in a solvent and as the solvent, one or moreselected from the group consisting of methylenechloride, dioxane,benzene and toluene, preferably methylenechloride, may be mentioned. Thereaction is usually carried out at room temperature or under warming andthe reaction is completed at room temperature for about 2 hours.

The compound of formula (4) used as a starting material in the aboveprocess for preparation of the compound of formula (1) according to thepresent invention may be produced by reacting a 2-hydroxyacetophenonederivative of the following formula (7)

wherein R₁, R₂, R₃, and R₄ are defined as previously described, with acompound of the following formula (8):

wherein R₆ and R₇ are defined as previously described, in the presenceof a base in a solvent.

Especially, the compound of formula (4a) can be prepared by reacting thecompound of the formula (7) with piperonal of formula (8a)

according to the above method.

The above reaction is depicted in the following Scheme (5).

wherein R₁, R₂, R₃, R₄, R₆ and R₇ are defined as previously described.

In the reaction according to Scheme 5, the compound of formula (4) isprepared by coupling the 2-hydroxyacetophenone derivative of formula (7)with the compound of formula (8) in an amount of 1 to 3 equivalents,preferably 3 equivalents. As the solvent which can be used, one or moreselected from the group consisting of water, methanol, ethanol,propanol, butanol and dioxane may be exemplified, and methanol, ethanolor aqueous ethanol solution (80%) is more preferable. As the base, oneor more selected from the group consisting of sodium hydroxide,potassium hydroxide, calcium hydroxide, sodium carbonate, potassiumcarbonate and calcium carbonate, preferably sodium hydroxide, may bementioned. The amount of base is not particularly restricted, however itis generally used in an amount of 2 to 5 equivalents, preferably 3equivalents with respect to the compound of formula (7). The reaction isusually carried out at room temperature or under warming and reactiontime is variable according to the kind of used solvent or base used, orreaction temperature. The reaction is usually completed at roomtemperature for about 15 hours.

In the processes as explained in above, the reaction conditionsincluding the amount of reactants, reaction temperature, reaction time,etc. are easily determined depending on the reactants selected by aperson having ordinary skill in this art. In general, as for solvent,any one can be used unless it adversely affect the reaction. Thereaction temperature may be changeable in variety, however the reactionis preferably carried out at temperatures ranging from 0 to 120° C.

The free compound of formula (1) prepared in the reaction according tothe present invention may be converted into the above-mentioned salt ina conventional manner well-known in the art. In addition, after thereaction is completed, the product may be isolated or purified byconventional work up procedures such as chromatography,recrystallization, etc.

The compound of the present invention prepared according to the abovemethod has an inhibitory activity against CDK, and thus may be put to agood use as an anti-cancer agent. Accordingly, another object of thepresent invention is to provide an anti-cancer agent or an agent fortreating neurodegenerative disease which comprises the compound offormula (1), pharmaceutically acceptable salt, hydrate, solvate orisomer thereof as an active ingredient together with pharmaceuticallyacceptable carrier.

In case the compound of the present invention is administered forclinical purpose, it is preferably administered in an amount rangingfrom 0.01 to 50 mg/kg of body weight a day. The total daily dosage maybe administered in one time or over several times. However, the specificdosage for a specific patient can be varied according to the specificcompound used, body weight of the subject patient, sex, hygieniccondition, diet, time or method of administration, excretion rate,mixing ratio of the medicine, severity of the disease to be treated,etc.

The compound of the present invention may be administered in the form ofinjections or oral preparations. Injections such as sterilized aqueousor oily suspension for injection may be prepared by using suitabledispersing agent, humectant or suspension agent according to the knownmethod. As solvents to be used for preparing injections, water, Ringer'sfluid and isotonic NaCl solution can be mentioned, and sterilized fixingoil is also used as the solvent or suspension medium. Anynon-stimulative fixing oil including mono- or di-glyceride can be usedfor this purpose, and also fatty acid such as oleic acid can be used forinjection formulation.

As the solid preparation for oral administration, capsules, tablets,pills, powders and granules, preferably capsules and tablets can bementioned. It is desirable for tablets and pills to be formulated intoenteric-coated preparation. Solid preparations may be prepared by mixingthe active compound of formula (1) according to the present inventionwith least one carrier selected from a group consisting of inertdiluents(e.g. sucrose. lactose, starch, etc.), lubricants(e.g. magnesiumstearate), disintegrators, and binders.

The present invention is more specifically explained by the followingprepartions and examples. However, it should be understood that thepresent invention is not limited to these examples in any manner.

Preparation 1 Synthesis of1-(3,5-Dichloro-2-hydroxy-phenyl)-3-(4-methoxy-phenyl)-propenone

1.0 g (4.8 mmol) of 3′,5′-dichloro-2′-hydroxyacetophenone was dissolvedin 30 ml of methanol solvent, and then 0.53 g of NaOH (13.2 mmol) wasadded thereto. The mixture was stirred for 30 minutes. 0.61 g (4.8 mmol)of 4-methoxybenzaldehyde was added thereto, the mixture was heated to50° C., and then it was stirred for 3 hours. After the reaction wascompleted, methanol was removed by distillation under reduced pressure.The residue was purified by silica gel column chromatography (eluent:n-hexane/ethylacetate=4/1, v/v) to give the title compound in a yield of57%.

¹H NMR (500 MHz, CDCl₃): δ 8.52 (m, 1H), 7.60-7.02 (m, 5H), 6.22-6.00(m, 2H), 3.90 (s, 3H); MS (FAB): 323 (M+H⁺).

Preparation 2 Synthesis of1-(2-Hydroxy-phenyl)-3-(4-methoxy-phenyl)-propenone

The title compound was obtained in a yield of 80% according to the sameprocedure as Preparation 1 using 1.0 g (7.3 mmol) of2′-hydroxyacetophenone and 0.99 g (7.3 mmol) of 4-methoxybenzaldehyde.

¹H NMR (500 MHz, CDCl₃): δ 7.44-6.66 (m, 8H), 6.21-6.01 (m, 2H), 3.89(s, 3H); MS (FAB): 255 (M+H⁺).

Preparation 3 Synthesis of3-(4-Chloro-phenyl)-1-(2-hydroxy-4-methoxy-phenyl)-propenone

The title compound was obtained in a yield of 77% according to the sameprocedure as Preparation 1 using 1.0 g (6.0 mmol) of2′-hydroxy-4′-methoxy acetophenone and 0.84 g (6.0 mmol) of4-chlorobenzaldehyde.

¹H NMR (500 MHz, CDCl₃): δ 7.55-6.46 (m, 7H), 6.42-6.21 (m, 2H), 3.99(s, 3H); MS (FAB): 289 (M+H⁺).

Preparation 4 Synthesis of 2-(4-Chloro-phenyl)-7-methoxy-chroman-4-one

0.1 g (0.35 mmol) of3-(4-chloro-phenyl)-1-(2-hydroxy-4-methoxy-phenyl)-propenone synthesizedin Preparation 3 was refluxed in solvent of trifluoroacetic acid(TFA)for a day, and TFA was removed by distillation under reduced pressure.The residue was purified by silica gel column chromatography (eluent:n-hexane/ethylacetate=5/1, v/v) to give the title compound in a yield of83%.

¹H NMR (500 MHz, CDCl₃): δ 7.86 (d, 1H, J=8.7 Hz), 7.42 (m, 4H), 6.62(d, 1H, J=2.4 Hz), 6.49 (s, 1H), 5.45 (m, 1H), 3.90 (s, 3H), 2.98 (dd,1H, J=12.7 Hz, J=16.6 Hz), 2.80 (dd, 1H, J=12.9 Hz, J=16.6 Hz); MS(FAB): 289 (M+H⁺).

Preparation 5 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(5-chloro-2-hydroxyphenyl)-2-propen-1-one

1 g (5.86 mmol) of 5-chloro-2-hydroxyacetophenone, 3 molar equivalentsof piperonal, and 3 molar equivalents of sodium hydroxide was mixed in15 ml of aqueous 80% ethanol solution, and then the mixture was stirredat room temperature for 15 hours. After the reaction was completed, 50ml of water was added thereto, and the mixture was stirred for about 10minutes. The obtained pale yellow solid was filtered, washed with waterand diethylether, and dried to give 1.42 g (Yield 80%) of the titlecompound.

¹H NMR (CDCl₃, ppm); δ 9.80 (1H, br s), 7.84 (1H, s), 7.43 (2H, m), 7.33(1H, s), 7.19 (1H, m), 6.98 (3H, m), 6.07 (2H, s); FAB MS (m/e)=303[M⁺+1],

Preparation 6 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(5-bromo-2-hydroxyphenyl)-2-propen-1-one

1.5 g (Yield 93%) of the title compound was obtained according to thesame procedure as Preparation 5 except that 1 g (4.65 mmol) of5-bromo-2-hydroxyacetophenone was used instead of 5-chloro-2-hydroxyacetophenone.

¹H NMR (CDCl₃, ppm); δ 7.99 (1H, s), 7.88 (1H, d), 7.55 (1H, d), 7.37(1H, d), 7.21-7.17 (2H, m), 6.94 (1H, d), 6.88 (1H, d); FAB MS (m/e)=348[M⁺+1].

Preparation 7 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(2-hydroxy-5-methoxyphenyl)-2-propen-1-one

1.3 g (Yield 72%) of the title compound was obtained according to thesame procedure as Preparation 5 except that 1 g (6.02 mmol) of5-methoxy-2-hydroxyacetophenone was used instead of 5-chloro-2-hydroxyacetophenone.

¹H NMR (CDCl₃, ppm); δ 7.85 (1H, d), 7.40 (1H, d), 7.33 (1H, s), 7.15(3H, m), 7.00-6.80 (3H, m), 6.07 (2H, s), 3.84 (3H, s); FAB MS (m/e)=299[M⁺+1].

Preparation 8 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(5-fluoro-2-hydroxyphenyl)-2-propen-1-one

1.6 g (Yield 86%) of the title compound was obtained according to thesame procedure as Preparation 5 except that 1 g (6.49 mmol) of5-fluoro-2-hydroxyacetophenone was used instead of 5-chloro-2-hydroxyacetophenone.

¹H NMR (CDCl₃, ppm); δ 7.85 (1H, s), 7.80 (1H, d), 7.55 (1H, d), 7.37(1H, d), 7.21-7.17 (2H, m), 6.94 (1H, d), 6.88 (1H, d); FAB MS (m/e)=287[M⁺+1].

Preparation 9 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(5-methyl-2-hydroxyphenyl)-2-propen-1-one

1.7 g (Yield 90%) of the title compound was obtained according to thesame procedure as Preparation 5 except that 1 g (6.66 mmol) of5-methyl-2-hydroxyacetophenone was used instead of 5-chloro-2-hydroxyacetophenone.

¹H NMR (CDCl₃, ppm); δ 7.73 (1H, s), 7.69 (1H, d), 7.55 (1H, d), 7.37(1H, d), 7.15-7.25 (2H, m), 6.92 (1H, d), 6.85 (1H, d); FAB MS (m/e)=283[M⁺+1].

Preparation 10 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(3,5-dichloro-2-hydroxyphenyl)-2-propen-1-one

1.4 g (Yield 85%) of the title compound was obtained according to thesame procedure as Preparation 5 except that 1 g (4.8 mmol) of3,5-dichloro-2-hydroxyacetophenone was used instead of5-chloro-2-hydroxyacetophenone.

¹H NMR (DMDO-d₆, ppm); δ 8.57 (1H, br s), 8.11 (1H, s), 8.06 (1H, d),7.88 (1H, d), 7.78 (1H, s), 7.42 (1H, d), 7.04 (1H, d), 6.13 (2H, s);FAB MS (m/e)=337 [M⁺+1].

Preparation 11 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(3,5-dibromo-2-hydroxyphenyl)-2-propen-1-one

2.9 g (Yield 97%) of the title compound was obtained according to thesame procedure as Preparation 5 except that 2 g (6.8 mmol) of3,5-dibromo-2-hydroxyacetophenone was used instead of5-chloro-2-hydroxyacetophenone.

¹H NMR (DMDO-d₆, ppm); δ 8.57 (1H, br s), 8.08 (1H, s), 8.01 (1H, d),7.88 (1H, d), 7.78 (1H, s), 7.42 (1H, d), 7.04 (1H, d), 6.13 (2H, s);FAB MS (m/e)=427 [M⁺+1].

Preparation 12 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(3,5-difluoro-2-hydroxyphenyl)-2-propen-1-one

1.6 g (Yield 90%) of the title compound was obtained according to thesame procedure as Preparation 5 except that 1 g(5.8 mmol) of3,5-difluoro-2-hydroxyacetophenone was used instead of5-chloro-2-hydroxyacetophenone.

¹H NMR (DMDO-d₆, ppm); δ 8.59 (1H, br s), 8.12 (1H, s), 8.01 (1H, d),7.88 (1H, d), 7.78 (1H, s), 7.42 (1H, d), 7.04 (1H, d), 6.13 (211, s);FAB MS (m/e)=305 [M⁺+1].

Preparation 13 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(5-chloro-2-hydroxy-4-methylphenyl)-2-propen-1-one

0.77 g (Yield 90%) of the title compound was obtained according to thesame procedure as Preparation 5 except that 0.5 g (2.70 mmol) of4-methyl-5-chloro-2-hydroxyacetophenone was used instead of5-chloro-2-hydroxyacetophenone.

¹H NMR (CDCl₃, ppm); δ 7.85 (1N, d), 7.82 (1N, s), 7.38 (1H, d), 7.19(2H, m), 6.86 (2H, m), 6.07 (2H, s), 2.41 (3H, s); FAB MS (m/e)=317[M⁺+1].

Preparation 14 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(2-hydroxy-4-methoxyphenyl)-2-propen-1-one

1.3 g (Yield 72%) of the title compound was obtained according to thesame procedure as Preparation 5 except that 1 g (6.02 mmol) of4-methoxy-2-hydroxyacetophenone was used instead of5-chloro-2-hydroxyacetophenone.

¹H NMR (CDCl₃, ppm); δ 7.85 (1H, d), 7.40 (1H, d), 7.33 (1H, s), 7.15(3H, m), 7.00-6.80 (3H, m), 6.07 (2H, s), 3.84 (3H, s); FAB MS (m/e)=299[M⁺+1].

Preparation 15 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(2-hydroxy-3,4-dimethoxyphenyl)-2-propen-1-one

1.2 g (Yield 72%) of the title compound was obtained according to thesame procedure as Preparation 5 except that 1 g (5.1 mmol) of3,4-dimethoxy-2-hydroxyacetophenone was used instead of5-chloro-2-hydroxyacetophenone.

¹H NMR (CDCl₃, ppm); δ 7.85 (1H, d), 7.40 (1H, d), 7.33 (1H, s), 7.15(1H, m), 7.00-6.80 (3H, m), 6.07 (2H, s), 3.84 (6H, s); FAB MS (m/e)=329[M⁺+1].

Preparation 16 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(2-hydroxy-3-methoxyphenyl)-2-propen-1-one

1.2 g (Yield 67%) of the title compound was obtained according to thesame procedure as Preparation 5 except that 1 g (6.02 mmol) of3-methoxy-2-hydroxyacetophenone was used instead of5-chloro-2-hydroxyacetophenone.

¹H NMR (CDCl₃, ppm); δ 7.85 (1H, d), 7.40 (1H, m), 7.33 (1H, s), 7.15(1H, m), 7.00-6.80 (3H, m), 6.07 (2H, s), 3.84 (3H, s); FAB MS (m/e)=299[M⁺+1].

Preparation 17 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(2-hydroxy-4,5-dimethylphenyl)-2-propen-1-one

1.77 g (Yield 97%) of the title compound was obtained according to thesame procedure as Preparation 5 except that 1 g (6.09 mmol) of4,5-dimethyl-2-hydroxyacetophenone was used instead of5-chloro-2-hydroxyacetophenone.

¹H NMR (CDCl₃, ppm); δ 7.75 (1H, s), 7.62 (1H, s), 7.38 (1H, d), 7.19(2H, m), 6.86 (2H, m), 6.07 (2H, s), 2.41 (6H, s); FAB MS (m/e)=297[M⁺+1].

Preparation 18 Synthesis of3-(Benzo[1,3]dioxol-5-yl)-1-(2-hydroxy-6-methoxyphenyl)-2-propen-1-one

1.25 g (Yield 70%) of the title compound was obtained according to thesame procedure as Preparation 5 except that 1 g (6.02 mmol of6-methoxy-2-hydroxyacetophenone was used instead of5-chloro-2-hydroxyacetophenone.

¹H NMR (CDCl₃, ppm); δ 7.80-6.71 (m, 6H), 6.22-6.00 (m, 2H), 5.90 (s,2H), 3.83 (s, 3H); FAB MS (m/e)=299 [M⁺+1].

Preparation 19 Synthesis ofN-{3-[3-(Benzo[1,3]dioxol-5-yl)-2-propenoyl]-4-hydroxyphenyl}acetamide

7.0 g (36.23 mmol) of 5-acetamido-2-hydroxyacetophenone, 3 molarequivalents of piperonal and 3 molar equivalents (4.32 g, 108 mmol) ofof sodium hydroxide was mixtured in 50 ml of aqueous 80% ethanolsolution, and then stirred at room temperature for 20 hours. After thereaction was completed, 100 ml of water was added thereto, and themixture was further stirred for 10 minutes. The obtained white solid wasfiltered, washed with water and ethyl ether, and dried to give 9.46 g ofthe title compound in a yield of 80%.

¹H NMR (DMSO-d₆, ppm); δ 11.94 (1H, s), 9.86 (1H, s), 8.13 (1H, s),7.80-7.67 (3H, m), 7.52 (1H, s), 7.32 (1H, d), 7.03 (1H, d), 6.95 (1H,d), 6.12 (2H, s), 2.02 (3H, s); FAB MS (m/e)=326 [M⁺+1].

EXAMPLE 1 Synthesis of 2-(4-Chloro-phenyl)-7-methoxy-chromen-4-one(Compound 1)

50 mg (0.17 mmol) of 2-(4-chloro-phenyl)-7-methoxy-chroman-4-onesynthesized in Preparation 4 and 3.0 molar equivalents (0.12 g, 0.51mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was refuxed inbenzene solvent for a day, and then benzene was removed by distillationunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: n-hexane/ethylacetate=5/1, v/v) to give thetitle compound in a yield of 79%.

¹H NMR (500 MHz, CDCl₃): δ 8.12 (d, 1H, J=9.3 Hz), 7.84 (d, 2H, J=8.8Hz), 7.49 (d, 2H, 8.8 Hz), 7.00 (m, 2H), 6.72 (s, 1H), 3.95 (s, 3H); MS(FAB): 287 (M+H⁺).

EXAMPLE 2 Synthesis of 7-Methoxy-2-phenyl-chromen-4-one (Compound 2)

240 mg (0.89 mmol) of1-(2-hydroxy-4-methoxy-phenyl)-3-phenyl-propan-1,3-dione was dissolvedin acetic acid, and 0.73 g (8.9 mmol) of sodium acetate was addedthereto. The mixture was refluxed overnight. Acetic acid was removed bydistillation under reduced pressure, and then the residue was purifiedby silica gel column chromatography (eluent: n-hexane/ethylacetate=5/1,v/v) to give the title compound in a yield of 70%.

¹H NMR (500 MHz, CDCl₃): δ 8.20 (m, 1H), 7.91 (m, 2H), 7.55 (m, 3H),6.97 (m, 3H), 3.90 (s, 3H); MS (FAB): 253 (M+H⁺).

EXAMPLE 3 Synthesis of 7-Hydroxy-2-phenyl-chromen-4-one (Compound 3)

100 mg (0.4 mmol) of compound 7-methoxy-2-phenyl-chromen-4-one obtainedin Example 2 was dissolved in methylenechloride, and 2.0 molarequivalents of BBr₃ was added thereto. The mixture was stirred for 1hour. Methanol was added to the mixture, and then solvent was removed bydistillation under reduced pressure. The residue was purified by silicagel column chromatography (eluent: methylenechloride/methanol=5/95, v/v)to give the title compound in a yield of 64%.

¹N NMR (500 MHz, d₄-MeOH): δ 8.04 (m, 1H), 7.90 (m, 2H), 7.61 (m, 3H),6.92 (m, 2H), 6.72 (m, 1H); MS (FAB): 239 (M+H⁺).

EXAMPLE 4 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-5-methoxy-chromen-4-one (Compound 4)

100 mg (0.35 mmol) of3-(benzo[1,3]dioxol-5-yl)-1-(2-hydroxy-6-methoxyphenyl)-propenoneobtained in Preparation 18 was dissolved in 5 ml of methanol, and then 6ml of 10% NaOH and 3.9 ml of 30% H₂O₂ was added thereto. The mixture wasstirred for 1 hour. 20 ml of water was added to the mixture, and then 10ml of 10% HCl was added thereto, and then the mixture was extracted withethylacetate. The extracted ethylacetate solution was distilled underreduced pressure, and the residue was purified by silica gel columnchromatography (eluent n-hexane/ethylacetate=4/1, v/v) to give the titlecompound in a yield of 95%.

¹H NMR (500 MHz, d₄-MeOH): δ 7.70-6.72 (m, 6H), 6.00 (s, 2H), 3.92 (s,3H); MS (FAB): 3 13 (M+H⁺).

EXAMPLE 5 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-6-methoxy-chromen-4-one (Compound 5)

The reaction was conducted according to the same procedure as Example 4except that 100 mg (0.35 mmol) of3-(benzo[1,3]dioxol-5-yl)-1-(2-hydroxy-5-methoxy-phenyl)-propenoneobtained in Preparation 7 was used as a starting material. Then theresidue was purified by silica gel column chromatography (eluent:n-hexane/ethylacetate=4/1, v/v) to give the title compound in a yield of90%.

¹H NMR (500 MHz, d₄-MeOH): δ 7.56-6.62 (m, 6H), 6.08 (s, 2H), 3.89 (s,3H); MS (FAB): 313 (M+H⁺).

EXAMPLE 6 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-7-methoxy-chromen-4-one (Compound 6)

The reaction was conducted according to the same procedure as Example 4except that 100 mg (0.35 mmol) of3-(benzo[1,3]dioxol-5-yl)-1-(2-hydroxy-4-methoxy-phenyl)-propenoneobtained in Preparation 14 was used as a starting material. Then theresidue was purified by silica gel column chromatography (eluent:n-hexane/ethylacetate=4/1, v/v) to give the title compound in a yield of85%.

¹H NMR (500 MHz, d₄-MeOH): δ 7.30-6.79 (m, 6H), 6.00 (s, 2H), 3.90 (s,3H); MS (FAB): 313 (M+H⁺).

EXAMPLE 7 Synthesis of3-Hydroxy-7-methoxy-2-(4-methoxy-phenyl)-chromen-4-one (Compound 7)

The reaction was conducted according to the same procedure as Example 4except that 57 mg (0.2 mmol) of1-(2-hydroxy-4-methoxy-phenyl)-3-(4-methoxy-phenyl)-propenone was usedas a starting material. Then the residue was purified by silica gelcolumn chromatography (eluent: n-hexane/ethylacetate=4/1, v/v) to givethe title compound in a yield of 92%.

¹H NMR (500 MHz, d₄-MeOH): δ 7.60-6.70 (m, 7H), 3.90 (s, 3H), 3.87 (s,3H); MS (FAB): 299 (M+H⁺).

EXAMPLE 8 Synthesis of2-(4-Chloro-phenyl)-3-hydroxy-7-methoxy-chromen-4-one (Compound 8)

The reaction was conducted according to the same procedure as Example 4except that 200 mg (0.69 mmol) of3-(4-chloro-phenyl)-1-(2-hydroxy-4-methoxy-phenyl)-propenone obtained inPreparation 3 was used as a starting material. Then the residue waspurified by silica gel column chromatography (eluent:n-hexane/ethylacetate=4/1, v/v) to give the title compound in a yield of89%.

¹H NMR (500 MHz, d₄-MeOH): δ 7.50-6.80 (m, 7H), 3.92 (s, 3H); MS (FAB):303 (M+H⁺).

EXAMPLE 9 Synthesis of6-Chloro-3-hydroxy-2-(4-methoxy-phenyl)-8-nitro-chromen-4one (Compound9)

The reaction was conducted according to the same procedure as Example 4except that 170 mg (0.51 mmol) of1-(5-chloro-2-hydroxy-3-nitro-phenyl)-3-(4-methoxy-phenyl)-propenone wasused as a starting material. Then the residue was purified by silica gelcolumn chromatography (eluent: n-hexane/ethylacetate=2/1, v/v) to givethe title compound in a yield of 76%.

¹H NMR (500 MHz, d₄-MeOH): δ 8.00 (s, 1H), 7.67 (m, 1H), 7.47-6.78 (m,4H), 3.87 (s, 3H) MS (FAB): 348 (M+H⁺).

EXAMPLE 10 Synthesis of6,8-Dichloro-3-hydroxy-2-(4-methoxy-phenyl)-chromen-4-one (Compound 10)

The reaction was conducted according to the same procedure as Example 4except that 150mg (0.47 mmol) of1-(3,5-dichloro-2-hydroxy-phenyl)-3-(4-methoxy-phenyl)-propenoneobtained in Preparation 1 was used as a starting material. Then theresidue was purified by silica gel column chromatography (eluent:n-hexane/ethylacetate=4/1, v/v) to give the title compound in a yield of79%.

¹H NMR (500 MHz, d6-DMSO): δ 8.23-7.90 (m, 4H), 7.11 (m, 2H), 3.87 (s,3H); MS (FAB): 337 (M+H⁺).

EXAMPLE 11 Synthesis of 3-Hydroxy-2-(4-methoxy-phenyl)-chromen-4-one(Compound 11)

The reaction was conducted according to the same procedure as Example 4except that 220 mg (0.87 mmol) of1-(2-hydroxy-phenyl)-3-(4-methoxy-phenyl)-propenone obtained inPreparation 2 was used as a starting material. Then the residue waspurified by silica gel column chromatography (eluent:n-hexane/ethylacetate=4/1, v/v) to give the title compound in a yield of91%.

¹H NMR (500 MHz, d₆-DMSO): δ 8.20 (m, 3H), 7.81 (m, 2H), 7.45 (m, 1H),7.18 (m, 2H), 3.91 (s, 3H); MS (FAB): 269 (M+H⁺).

EXAMPLE 12 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-6-chloro-3-hydroxy-4H-chromen-4-one

1 g (3.31 mmol) of the compound obtained in Preparation 5 was dissolvedin 5 ml of methanol, and 2 ml of aqueous 10% sodium hydroxide solutionand 2 mg of 30% hydrogen peroxide solution were added thereto. Then themixture was stirred at room temperature for 3 hours. The mixture wasdiluted with 5 ml of water, and acidified with 4N of hydrochloric acid.Then the resulting product was filtered to give 0.83 g (Yield 80%) ofthe title compound as pale yellow solid.

¹H NMR (CDCl₃, ppm); δ 8.20 (1H, br s), 7.75 (1H, s), 7.70 (1H, d), 7.54(1H, d), 7.50 (1H, s), 6.99 (2H, m); FAB MS (m/e)=317 [M⁺+1].

EXAMPLE 13 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-6-bromo-3-hydroxy-4H-chromen-4-one

0.89 g (Yield 85%) of the title compound was obtained according to thesame procedure as Example 12 except that 1 g (2.89 mmol) of the compoundobtained in Preparation 6 was used instead of the compound obtained inPreparation 5.

¹H NMR (CDCl₃+DMSO-d₆, ppm); δ 8.47 (1H, s), 8.32 (1H, s), 7.95-7.75(3H, m), 6.96 (1H, d), 6.07 (2H, s); FAB MS (m/e)=362 [M⁺+1].

EXAMPLE 14 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-6-fluoro-3-hydroxy-4H-chromen-4-one

0.85 g (Yield 81%) of the title compound was obtained according to thesame procedure as Example 12 except that 1.0 g(3.48 mmol) of thecompound obtained in Preparation 8 was used instead of the compoundobtained in Preparation 5.

¹H NMR (CDCl₃, ppm); δ 8.30 (1H, br s), 7.79 (1H, s), 7.70 (1H, d), 7.54(1H, d), 7.50 (1H, s), 6.99 (2H, m); FAB MS (m/e)=301 [M⁺+1].

EXAMPLE 15 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-6-methyl-3-hydroxy-4H-chromen-4-one

1.3 g (Yield 82%) of the title compound was obtained according to thesame procedure as Example 12 except that 1.5 g (5.3 mmol) of thecompound obtained in Preparation 9 was used instead of the. compoundobtained in Preparation 5.

¹H NMR (CDCl₃, ppm); δ 7.78 (1H, br s), 7.45 (1H, s), 7.40 (1H, d), 7.34(1H, d), 7.30 (1H, s), 6.99 (2H, m); FAB MS (m/e)=297 [M⁺+1].

EXAMPLE 16 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-6,8-dichloro-3-hydroxy-4H-chromen-4-one

1.3 g (Yield 89%) of the title compound was obtained according to thesame procedure as Example 12 except that 1.4 g (4.1 mmol) of thecompound obtained in Preparation 10 was used instead of the compoundobtained in Preparation 5.

¹H NMR (CDCl₃, ppm); δ 10.00 (1H, br s), 8.46 (1H, s), 8.20 (1H, s),7.95 (1H, d), 7.75 (1H, s), 7.53 (1H, d), 6.15 (2H, s); FAB MS (m/e)=351[M⁺+1].

EXAMPLE 17 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-6,8-dibromo-3-hydroxy-4H-chromen-4-one

1.86 g (Yield 62%) of the title compound was obtained according to thesame procedure as Example 12 except that 2.9 g (6.79 mmol) of thecompound obtained in Preparation 11 was used instead of the compoundobtained in Preparation 5.

¹H NMR (CDCl₃, ppm); δ 10.05 (1H, br s), 8.35 (1H, s), 8.15 (1H, s),7.90 (1H, d), 7.75 (1H, s), 7.53 (1H, d), 6.15 (2H, s); FAB MS (m/e)=441[M⁺+1].

EXAMPLE 18 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-6,8-difluoro-3-hydroxy-4H-chromen-4-one

1.5 g (Yield 89%) of the title compound was obtained according to thesame procedure as Example 12 except that 1.6 g (5.2 mmol) of thecompound obtained in Preparation 12 was used instead of the compoundobtained in Preparation 5.

¹H NMR (CDCl₃, ppm); δ 10.00 (1H, br s), 8.37 (1H, s), 8.19 (1H, s),7.91 (1H, d), 7.75 (1H, s), 7.53 (1H, d), 6.15 (2H, s); FAB MS (m/e)=319[M⁺+1].

EXAMPLE 19 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-6chloro-3-hydroxy-7-methyl-4H-chromen-4-one

44 mg (Yield 85%) of the title compound was obtained according to thesame procedure as Example 12 except that 50 mg (157 pmol) of thecompound obtained in Preparation 13 was used instead of the compoundobtained in Preparation 5.

¹H NMR (CDCl₃, ppm); δ 8.20 (1H, br s), 7.75 (1H, s), 7.70 (1H, d), 7.54(1H, d), 7.50 (1H, s), 6.99 (2H, m); FAB MS (m/e)=331 [M⁺+1].

EXAMPLE 20 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-7,8-dimethoxy-4H-chromen-4-one

80 mg (Yield 76%) of the title compound was obtained according to thesame procedure as Example 12 except that 100 mg (303 pmol) of thecompound obtained in Preparation 15 was used instead of the compoundobtained in Preparation 5.

¹H NMR (CDCl₃, ppm); δ 7.87 (1H, d), 7.77 (1H, d), 7.56 (1H, s), 7.51(1H, m), 6.98 (1H, d), 6.07 (2H, s), 3.92 (6H, s); FAB MS (m/e)=343[M⁺+1].

EXAMPLE 21 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-8-methoxy-4H-chromen-4-one

80 mg (Yield 76%) of the title compound was obtained according to thesame procedure as Example 12 except that 100 mg (335 pmol) of thecompound obtained in Preparation 16 was used instead of the compoundobtained in Preparation 5.

¹H NMR (CDCl₃, ppm); δ 7.87 (1H, d), 7.77 (1H, d), 7.56 (1H, s), 7.51(1H, m), 7.31-7.26 (2H, m), 6.98 (1H, d), 6.07 (2H, s), 3.92 (3 H, s);FAB MS (m/e)=313 [M⁺+1].

EXAMPLE 22 Synthesis of2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-6,7-dimethyl-4H-chromen-4-one

95 mg (Yield 90%) of the title compound was obtained according to thesame procedure as Example 12 except that 100 mg (337 pmol) of thecompound obtained in Preparation 17 was used instead of the compoundobtained in Preparation 5.

¹H NMR (CDCl₃, ppm); δ 7.84 (1H, s), 7.37 (2H, m), 7.18 (1H, s), 6.91(1H, m), 6.07 (2H, s), 2.39 (6H, s); FAB MS (m/e)=311 [M⁺+1].

EXAMPLE 23 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]acetamide

4 g (12.3 mmol) of the compound obtained in Preparation 19 was dissolvedin 50 ml of methanol, and 10 ml of aqueous 10% sodium hydroxide solutionand 10 ml of 30% hydrogen peroxide solution were added thereto. Then themixture was stiffed at room temperature for 5 hours. The mixture wasdiluted with 50 ml of water, and acidified with 4N of hydrochloric acid.Then the resulting product was filtered to give 3.29 g (Yield 79%) ofthe title compound as pale yellow solid.

¹H NMR (DMSO-d₆, ppm); δ 10.24 (1H, br s), 9.49 (1H, br s), 8.40 (1H,s), 7.90-7.71 (4H, m), 7.12 (1H, d), 2.08 (3H, s); FAB MS (m/e)=340[M⁺+1].

EXAMPLE 24 Synthesis of6-amino-2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen-4-one

3 g (8.85 mmol) of the compound obtained in Example 23 was stirred in 30ml of aqueous 80% ethanol solution and 10 ml of aqueous 30% sulfuricacid solution at 120° C. for 18 hours. After the reaction was completed,the mixture was cooled to room temperature, and neutralized with conc.ammonia water. Then the obtained solid was filtered, washed with water,and dried to give 1.8 g of the title compound in a yield of 68%.

¹H NMR (CDCl₃, ppm); δ 7.85 (1H, d), 7.75 (1H, s), 7.39 (1H, d), 7.08(1H, d), 6.97 (2H, m), 6.05 (2H, s), 3.86 (2H, br s); FAB MS (m/e)=298[M⁺+1].

EXAMPLE 25 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl-1)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-methylbenzenesulfonamide

50 mg (168 pmol) of6-amino-2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen-4-one obtained inExample 24 was dissolved in 5 ml of methylenechloride, then 2 molarequivalents of 4-toluenesulfonyl chloride (p-TsCl) and 3 molarequivalents of triethyl amine were added thereto. The mixture wasreacted at room temperature for 10 hours. The resulting product wasconcentrated under reduced pressure, and separated by preparative TLC togive 34 mg of the title compound in a yield of 45%.

¹H NMR (CDCl₃, ppm); δ 7.79 (2H, d), 7.50-7.20 (8H, m), 6.99 (1H, d),6.05 (2H, s), 2.47 (3H, s). FAB MS (m/e)=452 [M⁺+1].

EXAMPLE 26 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-bromobenzenesulfonamide

100 mg (336 pmol) of6-amino-2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen-4-one obtained inExample 24 was dissolved in 3 ml of pyridine, and the mixture wasreacted with 2 molar equivalents of 4-bromobenzenesulfonylchloride atroom temperature for 5 hours. After the reaction was completed, theproduct was diluted with 10 ml. of water, and the obtained solid wasfiltered. Then the resulting product was washed with water andethylether, and dried to give 159 mg of the title compound in a yield of91.6%.

¹H NMR (MeOH-d₄, ppm); δ 8.69 (1H, s), 8.11 (1H, s), 7.92-7.70 (6H, m),7.58 (1H, m), 7.01 (1H, d), 6.06 (2H, s). FAB MS (m/e)=517 [M⁺+1].

EXAMPLE 27 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-3-bromobenzenesulfonamide

24 mg (Yield 69.4%) of the title compound was obtained according to thesame procedure as Example 26 except that 3-bromobenzenesulfonylchlorideand 20 mg (67 pmol) of6-amino-2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen4-one were usedinstead of 4-bromobenzenesulfonylchloride.

¹H NMR (DMSO-d₆, ppm); δ 10.70 (11H, br s), 9.55 (1H, s), 7.91 (1H, s),7.85 (1H, d), 7.80 (1H, d), 7.72 (4H, m), 7.50 (2H, m), 7.11 (1H, d),6.12 (2H, s). FAB MS (m/e)=517 [M⁺+1].

EXAMPLE 28 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2-naphthalenesulfonamide

27 mg (Yield 82.5%) of the title compound was obtained according to thesame procedure as Example 26 except that 2-naphthalenesulfonylchloridewas used instead of 4-bromobenzene sulfonylchlonrde.

¹H NMR (DMSO-d₆, ppm); δ 10.69 (1H, br s), 9.48 (1H, s), 8.45 (1H, s),8.15 (2H, m), 8.00 (1H, d), 7.78-7.55 (8H, m), 7.09 (1H, d), 6.11 (2H,s). FAB MS (m/e)=488 [M⁺+1].

EXAMPLE 29 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-5-(dimethylamino)-1-naphthalenesulfonamide

22 mg (Yield 61.7%) of the title compound was obtained according to thesame procedure as Example 26 except that5-dimethylamino-1-naphthalenesulfonylchloride(Dansyl chloride) was usedinstead of 4-bromobenzenesulfonylchloride.

¹H NMR (DMSO-d₆, ppm); δ 10.97 (1H, br s), 9.46 (1H, s), 8.44 (1H, d),8.38 (1H, d), 8.22 (1H, d), 7.75-7.61 (6H, m), 7.45 (1H, d), 7.26 (1H,d), 7.07 (1H, d), 6.11 (2H, s), 2.79 (6H, s). FAB MS (m/e)=531 [M⁺+1].

EXAMPLE 30 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2-(1-naphthyl)-ethanesulfonamide

32 mg (Yield 92.6%) of the title compound was obtained according to thesame procedure as Example 26 except that2-(1-naphthyl)-ethanesulfonylchloride was used instead of 4-bromobenzenesulfonylchloride.

¹H NMR (DMSO-d₆, ppm); δ 10.34 (1H, br s), 9.58 (1H, s), 7.98 (1H, s),7.90-7.70 (7H, m), 7.50-7.40 (4H, m), 7.13 (1H, d), 6.14 (2H, d), 3.47(2H, m), 3.30 (2H, m). FAB MS (m/e)=516 [M⁺+1].

EXAMPLE 31 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4,5-dibromo-2-thiophenesulfonamide

33 mg (Yield 82%) of the title compound was obtained according to thesane procedure as Example 26 except that 4,5-thiopheinesulfonyl chloridewas used instead of 4-bromobenzene sulfonylchloride.

¹H NMR (DMSO-d₆, ppm); δ 9.60 (1H, s), 7.85-7.74 (4H, m), 7.57 (2H, m),7.12 (1H, s), 6.16 (2H, s). FAB MS (m/e)=602 [M⁺+1].

EXAMPLE 32 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-[1,1′-biphenyl]-4-sulfonamide

34 mg (Yield 98.8%) of the title compound was obtained according to thesame procedure as Example 26 except that 4-biphenyl sulfonylchloride wasused instead of 4-bromobenzene sulfonylchloride.

¹H NMR (DMSO-d₆, ppm); δ 10.67 (1H, br s), 9.56 (1H, s), 8.00-7.47 (14H,m), 7.12 (1H, d), 6.12 (2H, s). FAB MS (m/e)=514 [M⁺+1].

EXAMPLE 33 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-5-(isooxazolyl)-2-thiophenesulfonamide

30 mg (Yield 87.7%) of the title compound was obtained according to thesame procedure as Example 26 except that 5(isooxazolyl)-2-thiophenesulfonylchloride was used instead of 4-bromobenzenesulfonylchloride.

¹H NMR (DMSO-d₆, pp); δ 11.00 (1H, br s), 9.58 (1H, s), 8.70 (1H, s),7.90-7.50 (7H, m), 7.15-7.07 (2H, m), 6.13 (2H, s). FAB MS (m/e)=511[M⁺+1 ].

EXAMPLE 34 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-5-(2-pyridinyl)-2-thiophenesulfonamide

30 mg (Yield 86%) of the title compound was obtained according to thesame procedure as Example 26 except that5-(2-pyridinyl)-2-thiophenesulfonylchloride was used instead of 4-bromobenzenesulfonylchloride.

¹H NMR (DMSO-d₆, ppm); δ 10.84 (1H, br s), 9.56 (1H, s), 8.53 (1H, s),8.00-7.70 (7H, m), 7.56 (2H, m), 7.40 (1H, m), 7.11 (1H, m), 6.12 (2H,s). FAB MS (m/e)=521 [M⁺+1].

EXAMPLE 35 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-3,4-difluorobenzenesulfonamide

22 mg (Yield 69.4%) of the title compound was obtained according to thesame procedure as Example 26 except that3,4-difluorobenzenesulfonylchloride was used instead of 4-bromobenzenesulfonylchloride.

¹H NMR (DMSO-d₆, ppm); δ 10.70 (1H, br s), 9.57 (1H, s), 7.82-7.52 (8H,m), 7.11 (1H, d), 6.13 (2H, s). FAB MS (m/e)=474 [M⁺+1].

EXAMPLE 36 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(trifluoromethyl)benzenesulfonamide

24 mg (Yield 70.8%) of the title compound was obtained according to thesame procedure as Example 26 except that4-(trifluoromethyl)benzenesulfonylchloride was used instead of 4-bromobenzenesulfonylchloride.

¹H NMR (DMSO-d₆, ppm); δ 10.84 (1H, br s), 9.57 (1H, s), 7.95 (4H, m),7.79-7.71 (4H, m), 7.52 (1H, d), 7.11 (1H, d), 6.13 (2H, s). FAB MS(m/e)=506 [M⁺+1].

EXAMPLE 37 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-chloro-3-nitrobenzenesulfonamide

81 mg (Yield 93.4%) of the title compound was obtained according to thesame procedure as Example 26 except that4-chloro-3-nitrobenzenesulfonylchloride and 50 mg (168 pmol) of6-amino-2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen-4-one were usedinstead of 4-bromo benzenesulfonylchloride.

²H NMR(DMSO-d₆, ppm); δ 10.90 (1H, br s), 9.58 (1H, s), 8.42 (1H, s),7.95 (2H, m), 7.80-7.70 (4H, m), 7.53 (1H, d), 7.12 (1H, d), 6.12 (2H,s). FAB MS (m/e)=517 [M⁺+1].

EXAMPLE 38 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-3-chloro-1-propanesulfonamide

61 mg (Yield 84.4%) of the title compound was obtained according to thesame procedure as Example 37 except that3-chloro-1-propanesulfonylchloride was used instead of 4-chloro-3-nitrobenzenesulfonylchloride.

¹H NMR (DMSO-d₆, ppm); δ 10.21 (1H, br s), 9.58 (1H, s), 7.89 (1H, s),7.81 (2H, m), 7.75 (1H, s), 7.62 (1H, d), 7.13 (1H, d), 6.13 (2H, s),3.72 (2H, m), 3.26 (2H, m), 2.12 (2H, m). FAB MS (m/e)=438 [M⁺+1].

EXAMPLE 39 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2,4-difluorobenzenesulfonamide

76 mg (Yield 95.2%) of the title compound was obtained according to thesame procedure as Example 37 except that2,4-difluorobenzenesulfonylchloride was used instead of 4-chloro-3-nitrobenzenesulfonylchloride.

¹H NMR (DMSO-d₆, ppm); δ (10.96 (1H, s), 9.54 (1H, s), 7.90 (1H, m),7.79-7.70 (4H, m), 7.54 (2H, m), 7.25 (1H, m), 7.11 (1, d), 6.12 (2H,s). FAB MS (m/e)=474 [M⁺+1].

EXAMPLE 40 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-fluorobenzenesulfonamide

72 mg (Yield 94%) of the title compound was obtained according to thesame procedure as Example 37 except that 4-fluorobenzenesulfonylchloride was used instead of 4-chloro-3-nitrobenzenesulfonylchloride.

¹H NMR (DMSO-d₆, ppm); δ 10.59 (1H, s), 9.55 (1H, s), 7.79-7.71 (6H, m),7.50 (1H, d), 7.39 (2H, m), 7.12 (1H, d), 6.12 (2H, s). FAB MS (m/e)=456[M+−1].

EXAMPLE 41 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinesulfonamide

49 mg (Yield 82.4%) of the title compound was obtained according to thesame procedure as Example 26 except that2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinesulfonylchlonrdeand 30 mg (101 pmol) of6-amino-2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen-4-one were usedinstead of 4-bromobenzene sulfonylchloride.

¹H NMR (DMSO-d₆, ppm); δ 10.65 (1H, br s), 9.54 (1H, s), 7.90-7.70 (5H,m), 7.60-7.50 (2H, m), 7.40 (1H, m), 7.11 (1H, d), 6.12 (2H, s), 4.78(2H, d), 3.76 (2H, d), 2.94 (2H, m). FAB MS (m/e)=589 [M⁺+1].

EXAMPLE 42 Synthesis of4-({[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6y]amino}sulfonyl)benzoicacid

47 mg (Yield 96%) of the title compound was obtained according to thesame procedure as Example 41 except that 4-chlorosulfonylbenzoic acidwas used instead of2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinesulfonylchloride.

¹H NMR (DMSO-d₆, ppm); δ 10.71 (1H, br s), 9.55 (1H, s), 8.07 (2H, d),7.86-7.70 (6H, m), 7.52 (1H, d), 7.11 (1H, d), 6.12 (2H, s). FAB MS(m/e)=482 [M⁺+1 ].

EXAMPLE 43 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-y]1,2,3,4-tetrahydro-7-isoquinolinesulfonamide

20 mg (34 pmol) of the compound obtained in Example 38 was dissolved inmethanol, 0.1 ml of aqueous 1N sodium hydroxiden solution was addedthereto, and the mixture was stirred at room temperature for 1 hours.The mixture was concentrated, diltuted with water, acidified with 1Nhydrochloric acid, and then neutralized with sodium bicarbonate. Theproduced solid was filtered, washed with water, and dried to give 14.4mg of the title compound in a yield of 85.8%.

¹H NMR (DMSO-d₆, ppm); δ 7.76-7.66 (4H, m), 7.48 (3H, m), 7.23 (1H, d),7.11 (1H, d), 6.12 (2H, s), 3.85 (2H, m), 2.92 (2H, m), 2.70 (2H, m).FAB MS (m/e)=493 [M⁺+1].

EXAMPLE 44 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-N′-cyclohexylsulfamide

30 mg (101 pmol) of6-amino-2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen-4-one obtained inExample 24 was dissolved in 3 ml of pyridine, and the mixture wasreacted with excess amount of cyclohexylamino sulfonylchloride at roomtemperature for 15 hours. After the reaction was completed, theresulting product was diluted with 10 ml of water. The produced solidwas filtered, washed with water and ethylether, and then dried to give 6mg of the title compound in a yield of 13%.

¹H NMR (DMSO-d₆, ppm); δ 7.82-7.55 (5H, m), 7.13 (1H, d), 6.13 (2H, s),3.15 (1H, m), 1.67-1.40 (4H, m), 1.20-1.05 (6H, m). FAB MS (m/e)=459[M⁺+].

EXAMPLE 45 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(4-morpholinyl)-3-nitrobenzenesulfonamide

10 mg (19.3 pmol) of the compound obtained in Example 37, excess amountof morpholine and potassium carbonate were introduced into 5 ml ofacetonitrile, and boiled for 4 hours. The mixture was cooled to roomtemperature, and ethylether was added thereto. The mixture was stirredfor 10 minutes. The produced solid was filtered, washed with water andethylether, and then dried to give 5 mg of the title compound in a yieldof 45.5%.

¹H NMR (DMSO-d₆, ppm); δ 10.60 (1H, br s), 9.55 (1H, br s), 8.16 (1H,s), 7.80-7.70 (5H, m), 7.53 (1H, d), 7.36 (1H, d), 7.11 (1H, d), 6.12(2H, s), 3.64 (4H, m), 3.10 (4H, m). FAB MS (m/e)=568 [M⁺+1].

EXAMPLE 46 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamide

20 mg (38.7 pmol) of the compound obtained in Example 37, excess amountof N-methylpiperazine and potassium carbonate were introduced into 5 mlof acetonitrile, and boiled for 4 hours. The mixture was cooled to roomtemperature, concentrated under reduced pressure, dissolved in 10%methanol/methylenechloride, and then filtered through silica gel pad.The filtrate was concentrated to give 4.5 mg of the title compound in ayield of 20%.

¹H NMR (DMSO-d₆, ppm); δ 89.50 (1H, br s), 8.13 (1H, s), 7.79-7.70 (5H,m), 7.52 (1H, m), 7.35 (1H, d), 7.11 (1H, d), 6.12 (2H, s), 3.10 (4H,m), 2.36 (4H, m), 2.17 (3H, s). FAB MS (m/e)=581 [M⁺+1].

EXAMPLE 47 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-benzamide

30 mg (101 pmol) of6-amino-2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen-4-one obtained inExample 24 was dissolved in 2 ml of methylenechloride, and the mixturewas reacted with 10 molar equivalents of benzoylchloride and excessamount of potassium carbonate at room temperature for 10 hours. Theresulting product was filtered, washed with methylenechloride and water,and dried to give 32 mg of the title compound in a yield of 79%.

¹H NMR (DMSO-d₆, ppm); δ 10.54 (1H, s), 9.55 (1H, br s), 8.61 (1H, s),8.17 (1H, d), 8.02 (2H, d), 7.85-7.78 (3H, m), 7.62-7.55 (2H, m) 7.14(1H, d), 6.14 (2H, s); FAB MS (m/e)=402 [M⁺+1].

EXAMPLE 48 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-chlorobenzamide

43.5 mg (Yield 99%) of the title compound was obtained according to thesame procedure as Example 47 except that 4-chloro benzoylchloride wasused instead of benzoylchloride.

¹H NMR (DMSO-d, ppm); δ 10.63 (1H, br s), 9.61 (1H, br s), 8.59 (1H, s),8.15 (1H, d), 8.05 (2H, d), 8.90-8.70 (3H, m), 7.65 (2H, d), 7.14 (1H,s), 6.14 (2H, s); FAB MS (m/e)=436 [M⁺+1].

EXAMPLE 49 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]3-N′-benzylurea

30 mg (101 pmol) of6-amino-2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen-4-one and 1.5molar equivalents of benzylisocyanate were stirred in 3 ml ofmethylenechloride at room temperature for 15 hours. The resultingproduct was filtered, washed with methylenechloride, and then dried togive 35.9 mg of the title compound in a yield of 82.5%.

¹H NMR (DMSO-d₆, ppm); δ 9.40 (1H, br s), 8.96 (1H, s), 8.24 (1H, s),7.85-7.65 (4H, m), 7.34 (2H, m) 7.25 (1H, m), 7.12 (1H, d), 6.80 (1H,m), 6.13 (2H, s), 4.33 (2H, d). FAB MS (m/e)=431 [M⁺+1].

EXAMPLE 50 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-N′-(4-bromophenyl)urea

34.8 mg (Yield 69.6%) of the title compound was obtained according tothe same procedure as Example 49 except that 4-bromophenylisocyanate wasused instead of benzylisocyanate.

¹H NMR (DMSO-d₆, ppm); δ 7.78 (1H, d), 7.72 (1H, s), 7.55-7.40 (4H, m),7.20-7.05 (4H, m), 6.13 (2H, s). FAB MS (m/e)=496 [M⁺+1].

EXAMPLE 51 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-N′-phenylurea

28.5 mg (Yield 67.8%) of the title compound was obtained according tothe same procedure as Example 49 except that phenylisocyanate was usedinstead of benzylisocyanate.

¹H NMR (DMSO-d₆, ppm); δ 9.10 (1H, s), 8.80 (1H, s), 8.31 (1H, s), 7.84(1H, d), 7.77 (1H, s), 7.72 (2H, s), 7.49 (1H, d), 7.29 (2H, m), 7.13(1H, d), 6.98 (1H, d), 6.14 (2H, s). FAB MS (m/e)=417 [M⁺+1].

EXAMPLE 52 Synthesis ofN-[2-(Benzo[1,3dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-N′-benzoylurea

36 mg (Yield 80%) of the title compound was obtained according to thesame procedure as Example 49 except that benzoylisocyanate was usedinstead of benzylisocyanate.

¹H NMR (DMSO-d₄, ppm); δ 11.1 (1H, s), 11.0 (1H, s), 9.55 (1H, s), 8.42(1H, m), 8.04 (2H, m), 7.88-7.56 (6H, m), 7.13 (2H, m), 6.14 (2H, s).FAB MS (m/e)=445 [M⁺+1].

EXAMPLE 53 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-N′-(3-bromophenyl)urea

36 mg (Yield 72%) of the title compound was obtained according to thesame procedure as Example 49 except that 3-bromophenyl isocyanate wasused instead of benzylisocyanate.

¹H NMR (DMSO-d₆, ppm); δ 9.50 (1H, br s), 9.09 (1H, s), 8.97 (1H, s),8.30 (1H, s), 7.88 (1H, s), 7.82 (1H, d), 7.76 (1H, s), 7.73 (2H, s),7.34 (1H, d), 7.25 (1H, t), 7.18 (1H, d), 7.12 (1H, d), 6.14 (1H, s).FAB MS (m/e)=496 [M⁺+1].

EXAMPLE 54 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-N′-(2,4-dichlorophenyl)urea

39 mg (Yield 79.6%) of the title compound was obtained according to thesame procedure as Example 49 except that 2,4-dichlorophenylisocyanatewas used instead of benzylisocyanate.

¹H NMR (DMSO-d₆, ppm); δ 9.75 (1H, s), 9.50 (1H, br s), 8.44 (1H, s),8.34 (1H, s), 8.23 (1H, d), 7.84-7.65 (5H, m), 7.42 (1H, d), 7.13 (1H,d), 6.14 (2H, s). FAB MS (m/e)=486 [M⁺+1].

EXAMPLE 55 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-N′-(3-cyanophenyl)urea

40 mg (Yield 89.6%) of the title compound was obtained according to thesame procedure as Example 49 except that 3-cyanophenylisocyanate wasused instead of benzylisocyanate.

¹H NMR (DMSO-d₆, ppm); δ 9.56 (1H, s), 9.15 (1H, s), 8.32 (1H, s), 8.01(1H, m), 7.84 (1H, d), 7.80-7.45 (6H, m), 7.14 (1H, d), 6.14 (2H, s).FAB MS (m/e)=442 [M⁺+1].

EXAMPLE 56 Synthesis ofN-[2-(Benzo[1,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-N′-(4-nitrophenyl)urea

37.5 mg (Yield 80.5%) of the title compound was obtained according tothe same procedure as Example 49 except that 4-nitrophenylisocyanate wasused instead of benzylisocyanate.

¹H NMR (DMSO-d₆, ppm); δ 9.57 (1H, s), 9.53 (1H, s), 8.33 (1H, s), 8.21(2H, m), 7.82-7.74 (6H, m), 7.13 (1H, d), 6.14 (2H, s). FAB MS (m/e)=462[M⁺+1].

EXAMPLE 57 Synthesis of6-Chloro-2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-4-one (Compound12)

10 mg (31.6 pmol) of the compound obtained in Example 12 was dissolvedin 2 ml of methylenechloride, 3 molar equivalents of boron tribromide(BBr₃) was added thereto, and then the mixture was stirred at roomtemperature for 2 hours. The remained boron tribromide (BBr₃) wasdecomposed with methanol. The residue was concentrated under reducedpressure, and purified by preparative TLC to give 7 mg of the titlecompound in a yield of 72%.

¹H NMR (MeOH-d₄, ppm); δ 8.09 (1H, s), 7.80 (1H, s), 7.70 (3H, m), 6.90(1H, d); FAB MS (m/e)=305 [M⁺+1].

EXAMPLE 58 Synthesis of6-Bromo-2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-4one (Compound 13)

7.8 mg (Yield 16%) of the title compound was obtained according to thesame procedure as Example 57 except that 50 mg (138 pmol) of thecompound obtained in Example 13 was used instead of the compoundobtained in Example 12.

¹H NMR (MeOH-d₄, ppm); δ 8.26 (1H, s), 7.83 (1H, d), 7.80 (1H, s), 7.72(1H, d), 7.60 (1H, d), 6.91 (1H, d); FAB MS (m/e)=350 [M⁺+1].

EXAMPLE 59 Synthesis of2-(3,4-Dihydroxyphenyl)-3,6-dihydroxy-4H-chromen-4-one (Compound 14)

The reaction was conducted according to the same procedure as Example 57except that 50 mg (159 pmol) of the compound obtained in Example 5instead of the compound obtained in Example 12 and 5.0 molar equivalentsof boron tribromide (BBr₃) were used. Then the resulting product wasseparated by preparative TLC to give 23 mg of the title compound in ayield of 51%.

¹H NMR (DMSO-d₆, ppm); δ 7.47-6.48 (6H, m); FAB MS (m/e)=287 [M⁺+1].

EXAMPLE 60 Synthesis of6-Amino-2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-4-one (Compound 15)

The reaction was conducted according to the same procedure as Example 57except that 10 mg (5 pmol) of the compound obtained in Preparation 35was used instead of the compound obtained in Example 12. The resultingproduct was concentrated, and the solid was produced from 10%methanol/methylenechloride solution. The produced solid was filtered togive 9.5 mg of the title compound in a yield of 99%.

¹H NMR (MeOH-d₄, ppm); δ 8.11 (1H, s), 7.85-7.82 (2H, m), 7.75-7.67 (2H,m), 7.62 (1H, d); FAB MS (m/e)=286 [M⁺+1].

EXAMPLE 61 Synthesis of2-(3,4-Dihydroxyphenyl)-3-hydroxy-6-methoxy-4H-chromen-4-one (Compound16)

The reaction was conducted according to the same procedure as Example 57except that 50 mg (159 pmol) of the compound obtained in Example 5instead of the compound obtained in Example 12 and 1.5 molar equivalentsof boron tribromide (BBr₃) were used. Then the resulting product wasseparated by preparative TLC to give 28 mg of the title compound in ayield of 60%.

¹H NMR (MeOH-d₄, ppm); δ 7.78 (1H, m), 7.65 (1H, m), 7.50 (2H, m), 6.91(1H, m), 6.80 (1H, m), 3.90 (3H, s); FAB MS (m/e)=301 [M⁺+1].

EXAMPLE 62 Synthesis of6-Fluoro-2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-4-one (Compound17)

40 mg (Yield 83%) of the title compound was obtained according to thesame procedure as Example 57 except that 50 mg (166 pmol) of thecompound obtained in Example 14 was used instead of the compoundobtained in Example 12.

¹H NMR (MeOH-d₄, ppm); δ 8.26 (1H, d), 7.83 (1H, t), 7.80 (1H, s), 7.72(1H, d), 7.60 (1H, d), 6.91 (1H, d); FAB MS (m/e)=289 [M⁺+1].

EXAMPLE 63 Synthesis of6-Methyl-2-(3,4-dihydroxyphenyl)-3-hydroxy-4f1-chromen-4-one (Compound18)

40 mg (Yield 83%) of the tide compound was obtained according to thesame procedure as Example 57 except that 50 mg (168 pmol) of thecompound obtained in Example 15 was used instead of the compoundobtained in Example 12.

¹H NMR (MeOH-d₄, ppm); δ 8.02 (1H, s), 7.63 (1H, d), 7.80 (1H, s), 7.72(1H, d), 7.60 (1H, d), 6.91 (1H, d), 2.54 (3H, s); FAB MS (m/e)=285[M⁺+1].

EXAMPLE 64 Synthesis of6,8-Dichloro-2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-4-one(Compound 19)

20 mg (Yield 69%) of the title compound was obtained according to thesame procedure as Example 57 except that 30 mg (85 pmol) of the compoundobtained in Example 16 was used instead of the compound obtained inExample 12.

¹H NMR (DMSO-d₆, ppm); δ 9.76 (1H, s), 9.72 (1H, s), 9.36 (1H, s), 8.33(1H, s), 8.15 (1, s), 7.83 (1H, s), 7.68 (1H, d), 6.93 (1H, d); FAB MS(m/e)=339 [M⁺+1].

EXAMPLE 65 Synthesis of6,8-Dibromo-2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-4-one (Compound20)

22.8 mg (Yield 78%) of the title compound was obtained according to thesame procedure as Example 57 except that 30 mg (68 pmol) of the compoundobtained in Example 17 was used instead of the compound obtained inExample 12.

¹H NMR (DMSO-d₆, ppm); δ 9.75 (1H, s), 9.69 (1H, s), 9.36 (1H, s), 8.33(1H, s), 8.15 (1H, s), 7.83 (1H, s), 7.68 (1H, d), 6.93 (1H, d); FAB MS(m/e)=429 [M⁺+1].

EXAMPLE 66 Synthesis of6,8-Difluoro-2-(3,4-dihydroxyplenyl)-3-hydroxy-4H-chromen-4-one(Compound 21)

25 mg (Yield 86%) of the title compound was obtained according to thesame procedure as Example 57 except that 30 mg (94 pmol) of the compoundobtained in Example 18 was used instead of the compound obtained inExample 12.

¹H NMR (DN4SO-d₆, ppm); δ (9.75 (1H, s), 9.69 (]H, s), 9.36 (1H, s),8.33 (1H, s), 8.15 (1H, s), 7.83 (1H, s), 7.68 (1H, d), 6.93 (1H, d);FAB MS (m/e)=307 [M⁺+1].

EXAMPLE 67 Synthesis of6Chloro-2-(3,4-dihydroxyphenyl)-3-hydroxy-7-methyl-4H-chromen-4-one(Compound 22)

21.0 mg (Yield 73%) of the title compound was obtained according to thesame procedure as Example 57 except that 30 mg (91 pmol) of the compoundobtained in Example 19 was used instead of the compound obtained inExample 12.

¹H NMR (MeOH-d₄, ppm); δ 8.07 (1H, s), 7.79 (1H, s), 7.70 (1H, d), 7.61(1H, s), 6.90 (1H, d), 2.52 (3H, s); FAB MS (m/e)=319 [M⁺+1].

EXAMPLE 68 Synthesis of2-(3,4-Dihydroxyphenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one (Compound23)

The reaction was conducted according to the same procedure as Example 57except that 50mg (159 pmol) of the compound obtained in Example 6instead of the compound obtained in Example 12 and 1.5 molar equivalentsof boron tribromide (BBr₃) were used. Then the resulting product wasseparated by preparative TLC to give 28 mg of the title compound in ayield of 60%.

¹H NMR (MeOH-d₄, ppm); δ 7.78 (1H, m), 7.65 (1H, m), 7.50 (2H, m), 6.91(1H, m), 6.80 (1H, m), 3.90 (3H, s); FAB MS (m/e)=301 [M⁺+1].

EXAMPLE 69 Synthesis of2-(3,4-Dihydroxyphenyl)-3,8-dihydroxy-7-methoxy-4H-chromen-4-one(Compound 24)

15 mg (Yield 54%) of the title compound was obtained according to thesame procedure as Example 57 except that 30 mg (87 pmol) of the compoundobtained in Example 20 was used instead of the compound obtained inExample 12.

¹H NMR (MeOH-d₄, ppm); δ 8.07 (1H, s), 7.79 (1H, s), 7.70 (1H, d), 7.61(1H, s), 6.90 (1H, d), 3.84 (3H, s); FAB MS (m/e)=317 [M⁺+1].

EXAMPLE 70 Synthesis of2-(3,4-Dihydroxyphenyl)-3,8-dihydroxy-4H-chromen-4-one (Compound 25)

16 mg (Yield 58%) of the title compound was obtained according to thesame procedure as Example 57 except that 30 mg (96 pmol) of the compoundobtained in Example 21 was used instead of the compound obtained inExample 12.

¹H NMR (MeOH-d₄, ppm); δ 8.07 (1H, s), 7.79 (1H, s), 7.70 (1H, d), 7.61(1H, s), 7.54 (1H, m), 6.90 (1H, d); FAB MS (m/e)=287 [M⁺+1].

EXAMPLE 71 Synthesis of2-(3,4-Dihydroxyphenyl)-6,7-dimethyl-3-hydroxy-4H-chromen-4one (Compound26)

25 mg (Yield 86%) of the title compound was obtained according to thesame procedure as Example 57 except that 30 mg (96 pmol) of the compoundobtained in Example 22 was used instead of the compound obtained inExample 12.

¹H NMR (MeOH-d₄, ppm); δ 8.07 (1H, s), 7.79 (1H, s), 7.70 (1H, d), 7.61(1H, s), 6.90 (1H, d), 2.52 (6H, s); FAB MS (m/e)=299 [M⁺+1].

EXAMPLE 72 Synthesis of2-(3,4-Dihydroxyphenyl)-3-hydroxy-5-methoxy-4H-chromen-4-one (Compound27)

The reaction was conducted according to the same procedure as Example 57except that 60 mg (190 pmol) of the compound obtained in Example 4instead of the compound obtained in Example 12 and 1.5 molar equivalentsof boron tribromide (BBr₃) were used. Then the resulting product wasseparated by preparative TLC to give 23 mg of the title compound in ayield of 40%.

¹H NMR (d₆-DMSO, ppm); δ 6 7.71-6.47 (m, 6H), 3.91 (s, 3H); FAB MS(m/e)=301 [M⁺+1].

EXAMPLE 73 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-methylbenzenesulfonamide(Compound 28)

20 mg (44.3 pmol) of the compound obtained in Example 25 was reactedwith excess amount of boron tribromide (BBr₃) in 3 ml of methylenechloride at room temperature for 3 hours. After the reaction wascompleted, the resulting product was concentrated under reducedpressure, and then was separated by preparative TLC using 10%methanol/methylenechloride solvent to give 2.8 mg of the title compoundin a yield of 14.3%.

¹H NMR (MeOH-d₄, ppm); δ 7.75-7.48 (7H, m), 7.21 (2H, d), 6.90 (1H, d),2.32 (3H, s). FAB MS (m/e)=440 [M⁺+1].

EXAMPLE 74 Synthesis of4-Bromo-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]benzenesulfonamide(Compound 29)

14 mg (Yield 71.5%) of the title compound was obtained according to thesame procedure as Example 73 except that 20 mg (38.7 pmol) of thecompound obtained in Example 26 was used instead of the compoundobtained in Example 25.

¹H NMR (DMSO-d₆, ppm); δ 7.73 (2H, m), 7.57 (3H, m), 7.46 (2H, m), 6.89(2H, m). FAB MS (m/e)=505 [M⁺+1].

EXAMPLE 75 Synthesis of3-Bromo-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]benzenesuIfonamide(Compound 30)

16 mg (Yield 54.5%) of the title compound was obtained according to thesame procedure as Example 73 using 30 mg (58.1 pmol) of the compoundobtained in Example 27.

¹H NMR (MeOH-d₄, ppm); δ 7.92 (1H, s), 7.78-7.67 (5H, m), 7.59 (1H, m),7.54 (1H, m), 7.39 (1H, m), 6.89 (1H, d). FAB MS (m/e)=517 [M⁺+1].

EXAMPLE 76 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2-naphthalenesulfonamide(Compound 31)

11 mg (Yield 41.7%) of the title compound was obtained according to thesame procedure as Example 73 using 27 mg (55.4 pmol) of the compoundobtained in Example 28.

¹H NMR (MeOH-d₄, ppm); δ 8.37 (1H, s), 7.96-7.53 (11H, m), 6.87 (1H, d).FAB MS (m/e)=476 [M⁺+1].

EXAMPLE 77 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-5-(dimethylamino)-1-naphthalenesulfonamide(Compound 32)

11 mg (Yield 51%) of the title compound was obtained according to thesame procedure as Example 73 using 22 mg (41.5 pmol) of the compoundobtained in Example 29.

¹H NMR (MeOH-d₄, ppm); δ 8.49 (1H, d), 8.42 (1H, d), 8.24 (1H, d),7.73-7.59 (4H, m), 7.47-7.41 (3H, m), 7.25 (1H, d), 6.86 (1H, d), 2.81(6H, s). FAB MS (m/e)=519 [M⁺+1].

EXAMPLE 78 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2-(1-naphthyl)-1-ethanesulfonamide(Compound 33)

9 mg (Yield 28.8%) of the title compound was obtained according to thesame procedure as Example 73 using 32 mg (62 pmol) of the compoundobtained in Example 30.

¹H NMR (MeOH-d₄, ppm); δ 7.96 (1H, s), 7.81-7.71 (5H, m), 7.61 (2H, s),7.36 (4H, m), 6.91 (1H, d), 3.55-3.50 (4H, m). FAB MS (m/e)=504 [M⁺+1].

EXAMPLE 79 Synthesis of4,5-Dibromo-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2-thiophenesulfonamide(Compound 34)

10 mg (Yield 50.9%) of the title compound was obtained according to thesame procedure as Example 73 using 20 mg (33.2 pmol) of the compoundobtained in Example 31.

¹H NMR (DMSO-d₆, ppm); δ 11.00 (H, br s), 9.40 (1H, br s), 7.79 (1H, s),7.71 (2H, m), 7.59-7.53 (3H, m), 6.89 (1H, d). FAB MS (m/e)=590 [M⁺+1].

EXAMPLE 80 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-[1,1′-biphenyl]-4-sulfonamide(Compound 35)

7.2 mg (Yield 21%) of the title compound was obtained according to thesame procedure as Example 73 using 35 mg (68.2 pmol) of the compoundobtained in Example 32.

¹H NMR (DMSO-d₆, ppm); δ 10.63 (1H, br s), 9.60 (1H, br s), 9.28 (2H, brs), 7.84-7.40 (1H, m), 6.87 (1H, d). FAB MS (m/e)=502 [M⁺ _(+1].)

EXAMPLE 81 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-5-(isooxazolyl)-2-thiophenesulfonamide(Compound 36)

18.7 mg (Yield 66%) of the title compound was obtained according to thesame procedure as Example 73 using 29 mg (56.8 pmol) of the compoundobtained in Example 33

¹H NMR (DMSO-d₆, ppm); δ 10.93 (1H, br s) 9.58 (1H, br s), 9.32 (1H, brs), 8.70 (1H, s), 7.84 (1H, s), 7.68 (3H, m), 7.60-7.50 (3H, m), 7.07(1H, s), 6.88 (1H, d). FAB MS (m/e)=499 [M⁺+1].

EXAMPLE 82 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-5-(2-pyridinyl)-2-thiophenesulfonamide(Compound 37)

29 mg (Yield 99%) of the title compound was obtained according to thesame procedure as Example 73 using 30 mg (57.6 pmol) of the compoundobtained in Example 34.

¹H NMR (DMSO-d₆, ppm); δ 10.80 (1H, s), 8.53 (1H, d), 7.98 (1H, d), 7.87(2H, m), 7.77 (1H, d), 7.69 (2H, m), 7.55 (3H, m), 7.38 (1H, m), 6.88(1H, m). FAB MS (m/e)=509 [M⁺+1].

EXAMPLE 83 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-3,4-difluorobenzenesulfonamide(Compound 38)

11.4 mg (Yield 53.1%) of the title compound was obtained according tothe same procedure as Example 73 using 22 mg (46.5 pmol) of the compoundobtained in Example 35.

¹H NMR (DMSO-d₆, ppm); δ 10.65 (1H, s), 9.58 (1H, s), 9.31 (1H, s), 9.29(1H, s), 7.82 (1H, t), 7.72-7.50 (7H, m), 6.88 (1H, d). FAB MS (m/e)=462[M⁺+1].

EXAMPLE 84 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(trifluoromethyl)benzenesulfonamide(Compound 39)

10 mg (Yield 85.5%) of the title compound was obtained according to thesame procedure as Example 73 using 12 mg (23.7 pmol) of the compoundobtained in Example 36.

¹H NMR (DMSO-d₆, ppm); δ 10.78 (1H, s), 7.95 (4H, m), 7.73-7.50 (5H, m),6.88 (1H, d). FAB MS (m/e)=494 [M⁺+1].

EXAMPLE 85 Synthesis of4-Chloro-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-3-nitrobenzenesulfonamide(Compound 40)

19 mg (Yield 97.3%) of the title compound was obtained according to thesame procedure as Example 73 using, 20 mg (38.7 pmol) of the compoundobtained in Example 37.

¹H NMR (DMSO-d₆, ppm), δ

10.84 (1H, s), 9.60 (1H, br s), 9.35 (1H, s), 9.30 (1H, br s), 8.41 (1H,s), 7.96 (2H, m), 7.74-7.66 (3H, m), 7.56-7.50 (2H, m), 6.89 (1H, d).FAB MS (m/e)=505 [M⁺+1].

EXAMPLE 86 Synthesis of3-Chloro-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-1-propanesulfonamide(Compound 41)

19 mg (Yield 97.8%) of the title compound was obtained according to thesame procedure as Example 73 using 20 mg (45.7 pmol) of the compoundobtained in Example 38.

¹H NMR (DMSO-d₆, ppm); δ 10.20 (1H, s), 9.30 (1H, br s), 7.89 (1H, s),7.72 (2H, m), 7.59 (2H, m), 6.90 (1H, d), 3.71 (2H, m), 3.26 (2H, m),2.12 (2H, m). FAB MS (m/e)=426 [M⁺+1].

EXAMPLE 87 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2,4-difluorobenzenesulfonamide(Compound 42)

9.4 mg (Yield 48.6%) of the title compound was obtained according to thesame procedure as Example 73 using 20 mg (42 pmol) of the compoundobtained in Example 39.

¹H NMR (DMSO-d₆, ppm); δ 10.94 (1H, s), 9.30 (1H, br s), 7.90 (1H, m),7.74 (1H, m), 7.68 (2H, m), 7.54 (3H, m), 7.25 (1H, m), 6.88 (1H, d).FAB MS (m/e)=462 [M⁺+1].

EXAMPLE 88 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-fluorobenzenesulfonamide(Compound 43)

5.2 mg (Yield 26.5%) of the title compound was obtained according to thesame procedure as Example 73 using 20 mg (44 pmol) of the compoundobtained in Example 40.

¹H NMR (DMSO-d₆, ppm); δ 10.57 (1H, br s), 9.60 (1H, br s), 9.30 (1H, brs), 7.79 (2H, m), 7.72 (3H, m), 7.50 (2H, m), 7.41 (2H, m), 6.88 (1H,d). FAB MS (m/e)=444 [M⁺+1].

EXAMPLE 89 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinesulfonamide(Compound 44)

3.5 mg (Yield 17.6%) of the title compound was obtained according to thesame procedure as Example 73 using 20 mg (34 pmol) of the compoundobtained in Example 41.

¹H NMR (DMSO-d₆, ppm); δ 9.70-9.00 (4H, br m), 7.74-7.20 (8H, m), 6.88(1H, d), 4.30 (2H, m), 3.80 (2H, m), 3.01 (2H, m). FAB MS (m/e)=577[M⁺+1].

EXAMPLE 90 Synthesis of4-({[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]amino}sulfonyl)benzoicAcid (Compound 45)

9.6 mg (Yield 49%) of the title compound was obtained according to thesame procedure as Example 73 using 20 mg (41.5 pmol) of the compoundobtained in Example 42.

¹H NMR (DMSO-d₆, ppm); δ 10.56 (1H, s), 9.30 (1H, br s), 8.10-7.50 (9H,m), 6.89 (1H, m). FAB MS (m/e)=470 [M⁺+1].

EXAMPLE 91 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-1,2,3,4-tetrahydro-7-isoquinolinesulfonamide(Compound 46)

7.8 mg (Yield 55.6%) of the title compound was obtained according to thesame procedure as Example 73 using 14.4 mg (29.2 pmol) of the compoundobtained in Example 43.

¹H NMR (DMSO-d₆, ppm); δ 10.64 (1H, s), 9.63 (1H, s), 9.29 (1H, br s),9.0 (1H, m), 7.74-7.40 (8H, m), 6.89 (1H, d), 4.30 (2H, m), 3.47 (2H,m), 3.00 (2H, m). FAB MS (m/e)=481 [M⁺+1].

EXAMPLE 92 Synthesis ofN-Cyclohexyl-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]sulfamide(Compound 47)

1.5 mg (Yield 25.8%) of the title compound was obtained according to thesame procedure as Example 73 using 6 mg (13 pmol) of the compoundobtained in Example 44.

¹H NMR (MeOH-d₄, ppm); δ 7.89-7.50 (5H, m), 6.91 (1H, d), 3.15 (1H, m),1.79-1.16 (10H, m). FAB MS (m/e)=447 [M⁺+1].

EXAMPLE 93 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(4-morpholinyl)-3-nitrobenzenesulfonamide(Compound 48)

5 mg (Yield 25.5%) of the title compound was obtained according to thesame procedure as Example 73 using 20 mg (35.2 pmol) of the compoundobtained in Example 45.

¹H NMR (MeOH-d₄, ppm); δ 7.92 (1H, s), 7.53 (31H, m), 7.45 (1H, d), 7.36(2H, m), 7.01 (1H, d), 6.65 (1H, d), 3.49 (4H, m), 2.90 (4H, m). FAB MS(m/e)=556 [M⁺+1].

EXAMPLE 94 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamide(Compound 49)

22.5 mg (Yield 76.5%) of the title compound was obtained according tothe same procedure as Example 73 using 30 mg (51.7 pmol) of the compoundobtained in Example 46.

¹H NMR (MeOH-d₄, ppm); δ 8.30 (1H, s), 7.90 (1H, m), 7.78 (2H, m), 7.69(1H, d), 7.60 (2H, m), 7.40 (1H, m), 6.89 (1H, d), 3.57 (4H, m), 3.40(4H, m), 2.94 (3H, s). FAB MS (m/e)=569 [M⁺+1].

EXAMPLE 95 Synthesis of3-amino-N-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(4-methyl-1-piperazinyl)benzenesulfonamide(Compound 50)

10 mg (17.6 pmol) of the compound obtained in Example 94 was dissolvedin 5 ml of methanol, catalytic amount of 10% Pd/C was added thereto, andthe mixture was reacted under 1atm of hydrogen gas at room temperaturefor 3 hours. The resulting product was filtered through celite pad, andwashed with methanol. The filtrate was concentrated, and dried to give6.4 mg of the title compound in a yield of 67.5%.

¹H NMR (MeOH-d₄, ppm); δ 7.77 (2H, d), 7.69 (1H, d), 7.55 (2H, m), 7.17(1H, s), 7.06 (1H, d), 7.01 (1H, d), 6.89 (1H, d), 3.34 (8H, m), 2.85(3H, s). FAB MS (m/e)=539 [M⁺+1].

EXAMPLE 96 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]acetamide(Compound 51)

20 mg (59pmol) of the compound obtained in Example 23 was dissolved in 2ml of methylenechloride, and the mixture was reacted with excess amountof boron tribromide (BBr₃) at room temperature for 3 hours. Theresulting product was concentrated. Then the produced solid was washedwith methylenechloride and 10% methanol/methylenechloride, filtered, anddried to give 18 mg of the title compound in a yield of 93%.

¹H NMR (MeOH-d₄, ppm); δ 8.32 (1H, s), 7.94 (1H, d), 7.80 (1H, s), 7.72(1H, d), 7.69 (1H, d), 6.91 (1H, d), 2.16 (314, s). FAB MS (m/e)=328[M⁺+1].

EXAMPLE 97 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]benzamide(Compound 52)

24.8 mg (Yield 85%) of the title compound was obtained according to thesame procedure as Example 96 except that 30 mg (74.8 pmol) of thecompound obtained in Example 47 was used instead of the compoundobtained in Example 23.

¹H NMR (MeOH-d₄+DMSO-d₆, ppm); δ 11.07 (1H, s), 9.25 (1H, s), 8.80 (1H,d), 8.69 (2H, d), 8.51 (1H, s), 8.39 (2H, m), 8.30-8.20 (3H, m), 7.63(1H, d). FAB MS (m/e)=390 [M⁺+1].

EXAMPLE 98 Synthesis of4-Chloro-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]benzamide(Compound 53)

13 mg (Yield 66.7%) of the title compound was obtained according to thesame procedure as Example 96 except that 20 mg (46 pmol) of the compoundobtained in Example 48 was used instead of the compound obtained inExample 23.

¹H NMR (DMSO-d₆, ppm); δ 10.59 (1H, s), 9.25 (1H, br s), 8.57 (1H, s),8.16 (1H, d), 8.05 (2H, d), 7.75 (2H, m), 7.65 (1H, d), 7.63 (1H, d),6.91 (1H, d). FAB MS (m/e)=424 [M⁺+1].

EXAMPLE 99 Synthesis ofN-Benzyl-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]urea(Compound 54)

30 mg (69.7 pmol) of the compound obtained in Example 49 was introducedinto 3 ml of methylenechloride, and the mixture was reacted with 3 molarequivalents of boron tribromide (BBr₃) at room temperature for 3 hours.The remained boron tribromide (BBr₃) was decomposed with methanol, andthe residue was concentrated under reduced pressure. The produced solidwas washed with methylenechloride and 10% methanol/methylenechloride,filtered, and then dried to give 23 mg of the title compound in a yieldof 78.9%.

¹H NMR (MeOH-d₄, ppm); δ 8.83 (1H, s), 8.50 (3H, m), 8.38 (1H, d), 8.29(1H, d), 8.04 (4H, m), 7.61 (1H, d). FAB MS (m/e)=419 [M⁺+1].

EXAMPLE 100 Synthesis ofN-(4-Bromophenyl)-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]urea(Compound 55)

18 mg (Yield 92.5%) of the title compound was obtained according to diesame procedure as Example 99 except that 20 mg (40 pmol) of the compoundobtained in Example 50 was used instead of the compound obtained inExample 49.

¹H NMR (DMSO-d₆, ppm); δ 7.73 (2H, m), 7.57 (3H, m), 7.46 (2H, m), 7.30(1H, m), 6.89 (2H, m). FAB MS (m/e)=484 [M⁺+1].

EXAMPLE 101 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-N′-phenylurea(Compound 56)

15 mg (Yield 81%) of the title compound was obtained according to thesame procedure as Example 99 except that l9 mg (45.6 pmol) of thecompound obtained in Example 51 was used instead of the compoundobtained in Example 49.

¹H NMR (MeOH-d₄, ppm); δ 8.13 (1H, s), 7.91 (1H, d), 7.81 (1H, s), 7.72(1H, m), 7.62 (1H, s), 7.45 (2H, d), 7.29 (2H, m), 7.04 (1H, m), 6.91(1H, m). FAB MS (m/e)=405 [M⁺+1].

EXAMPLE 102 Synthesis ofN-Benzyl-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]urea(Compound 57)

18 mg (Yield 77%) of the title compound was obtained according to thesame procedure as Example 99 except that 24 mg (54 pmol) of the compoundobtained in Example 52 was used instead of the compound obtained inExample 49.

¹H NMR (DMSO-d₆, ppm); δ 11.14 (1H, s), 11.02 (1H, s), 8.40 (1H, s),8.05 (1H, d), 7.90 (1H, d), 7.75-7.54 (6H, m), 6.91 (1H, d). FAB MS(m/e)=433 [M⁺+1].

EXAMPLE 103 Synthesis ofN-(3-Bromophenyl)-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]urea(Compound 58)

20 mg (Yield 85.5%) of the title compound was obtained according to thesame procedure as Example 99 except that 24 mg (48.4 pmol) of thecompound obtained in Example 53 was used instead of the compoundobtained in Example 49.

¹H NMR (MeOH-d₄, ppm); δ 8.14 (1H, s), 7.92 (1H, d), 7.81 (2H, m), 7.13(1H, d), 7.64 (1H, d), 7.36 (1H, d), 7.20-7.17 (2H, m), 6.91 (1H, d).FAB MS (m/e)=484 [M⁺+1].

EXAMPLE 104 Synthesis ofN-(2,4-Dichlorophenyl)-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]urea(Compound 59)

25 mg (Yield 98.5%) of the title compound was obtained according to thesame procedure as Example 99 except that 26 mg (53.6 pmol) of thecompound obtained in Example 54 was used instead of the compoundobtained in Example 49.

¹H NMR (MeOH-d₄, ppm); δ 8.20 (2H, m), 7.90 (1H, d), 7.81 (1H, s), 7.73(1H, d), 7.65 (1H, d), 7.48 (1H, s), 7.32 (1H, d), 6.91 (1H, d). FAB MS(m/e)==474 [M⁺+1].

EXAMPLE 105 Synthesis ofN-(3-Cyanophenyl)-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]urea(Compound 60)

4.9 mg (Yield 50.4%) of the title compound was obtained according to thesame procedure as Example 99 except that 10 mg (22.6 pmol) of thecompound obtained in Example 55 was used instead of the compoundobtained in Example 49.

¹H NMR (DMSO-d₆, ppm); δ 9.19 (1H, s), 9.13 (1H, s), 8.82 (1H, s), 8.31(1H, s), 8.01 (1H, s), 7.93 (1H, s), 7.89 (1H, s), 7.74-7.34 (7H, m),6.90 (1H, s). FAB MS (m/e)=430 [M⁺+1].

EXAMPLE 106 Synthesis ofN-[2-(3,4-Dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-N′-(4-nitrophenyl)urea(Compound 61)

24 mg (Yield 98%) of the title compound was obtained according to thesame procedure as Example 99 except that 25 mg (54 pmol) of the compoundobtained in Example 56 was used instead of the compound obtained inExample 49.

¹H NMR (DMSO-d₆, ppm); δ 9.57 (1H, s), 9.28 (1H, s), 8.32 (1H, s), 8.22(2H, d), 7.74-7.60 (6H, m), 6.90 (1H, d). FAB MS (m/e)=450 [M₊+1].

EXAMPLE 107 Synthesis ofN-(4-Aminophenyl)-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]urea(Compound 62)

16 mg (35.6 pmol) of the compound obtained in Example 106 was dissolvedin 2 ml of methanol, catalytic amount of 10% Pd/C was added thereto, andthe mixture was reacted under 1atm of hydrogen gas for 3 hours. Theresulting product was filtered through celite pad, and washed withmethanol. Then the filtrate was concentrated under reduced pressure togive 3.5 mg of the title compound in a yield of 23%.

¹H NMR (DMSO-d₆, ppm); δ 9.55 (1H, s), 9.28 (1H, s), 9.20 (1H, s), 8.93(1H, s), 8.43 (1H, s), 8.25 (1H, s), 7.73-7.59 (4H, m), 7.21 (2H, d),6.90 (1H, d), 6.69 (2H, d). FAB MS (m/e)=420 [M⁺+1].

Experimental Example 1

Analysis of inhibitory activity against CDK2/cyclin A and CDK4/cyclin D1enzyme.

The inhibitory activity against CDK2 is measured by referring toKitagawa, M. et al., Oncogene 9:2549, 1994 and the inhibitory activityagainst CDK4 is measured by referring to Carlson, B. A. et al., CancerResearch 56:2473,1996.

As for CDK2, either the extract from the insect cell infected both withbaculovirus which expresses CDK2 gene and baculovirus which expressescyclin A gene or the active enzyme which had been purified therefrom wasused. CDK4 enzyme was also obtained from the insect cell infected bothwith baculovirus expressing CDK4 gene and baculovirus expressing cyclinD1 gene. As the substrate for CDK2, either histon H1 or Rb protein wasused. Rb protein was also used as the substrate for CDK4.

Specifically the activities of enzymes CDK2/cyclin A and CDK4/cyclin D1were determined according to the following procedure.

100 ng of enzyme was reacted in a total 1000 μl of 20 mM Tris (pH 8.0),100 mM NaCl, 10 mM MgCl₂ buffer solution containing 20 μg of GST-RBprotein, 100 μM of ATP and 5 μCi of P₃₂-γ-ATP at 30° C. for 30 minutes.Then, the enzyme reaction was stopped by adding EDTA to a concentrationof 20 mM. Subsequently, 30 μl of 50% glutathione bead (purchased fromPharmacia) was added to attach GST-RB to the bead, which was washedthree times with 20mM Tris (pH 8.0), 100 mM NaCl, 10 mM EDTA solution,and then scintillation counting was carried out. To analyze theinhibitory activity of the compound, the inhibitor having a properconcentration was added to the enzyme reaction solution, and then theenzyme activity was measured according to the above method.

The inhibitory activity of the compound of formula (1) according to thepresent invention against CDK2 and CDK4 is represented as IC₅₀ value.The test results are shown in the following Table 1. The compounds whichare not included in Examples(compound 63, 64, 65 and 66) weresynthesized and purified according to the same procedure as examples,and then IC₅₀ thereof was measured.

TABLE 1 Co. CDK2 CDK4 No. Structure M.W. IC₅₀ (μM) IC₅₀ (μM) 1

286 >200 >200 2

252 >200 >200 3

238 >200 >200 4

312 >100 >100 5

312 >100 >100 6

312 >100 >100 7

298 >100 >100 8

302 >100 >100 9

347 >100 >100 10

336 >100 >100 11

268 >100 >100 12

305 <5 <10 13

350 <5 <5 14

286 <5 <5 15

285 <5 <5 16

300 <10 <10 17

289 <10 <10 18

285 <10 <10 19

339 <10 <10 20

429 <5 <5 21

307 <10 <10 22

319 <10 <10 23

300 <30 <30 24

317 <10 <10 25

287 <10 <10 26

299 <10 <10 27

300 <10 <10 28

439 56 7.8 29

504 17.8 1.8 30

504 14 2.1 31

475 35.5 4.2 32

518 35.5 4.2 33

503 63 5 34

589 3.0 1.0 35

501 4.0 2.0 36

498 12.0 3.5 37

508 12.5 4.2 38

461 19.0 2.6 39

493 55.0 6.4 40

504 80.0 2.5 41

425 20.0 6.5 42

461 46.0 4.3 43

443 8.6 2.1 44

576 4.1 2.3 45

469 28.2 6.0 46

480 82.0 6.3 47

446 65.0 2.0 48

555 200 0.94 49

568 31 1.6 50

538 >200 30 51

327 5.6 5.6 52

389 23 6 53

423 >100 5.6 54

418 2.3 2.8 55

483 1.3 0.7 56

404 5.0 4.2 57

432 22.4 18.0 58

483 4.2 4.2 59

473 20.0 10.0 60

429 4.7 2.7 61

449 5.6 1.7 62

419 2.6 2.3 63

270 <10 <10 64

286 <5 <10 65

302 <50 <50 66

302 <10 <10

As can be seen from the results described in the above Table 1, sincenovel flavone derivative of formula (1) according to the presentinvention has an excellent inhibitory activity against CDK2 and CDK4, itcan be used advantageously as an anti-cancer agent.

In addition, it can be useful as an agent for treating neurodegenerativedisease because it has an inhibitory activity against CDK5 which is ahomology with CDK2 and is included in the same family (Ref.: John Leu etal., “Neuronal CDC2-like kinase”, TIBS., January 1995, pp33˜37).

Experimental Example 2 Acute Toxicity Experiment

The acute oral toxcities of the compounds 14, 17, 28, 39, 51 and 57 eachof which is obtained in Examples 14, 17, 73,84, 96 and 102, respectivelyare investigated in the following.

Solutions containing a compound in several different concentrations fromeach other were prepared, and they were administered orally to ICR malemouse with a dose of 10 ml/kg.

After administration, lethality and symptoms for 7 days were observed,and LD₅₀ (mg/kg) was calculated according to Litchfield-Wilcoxon'method. The result are represented in the following Table 2.

TABLE 2 Test Compound No. LD₅₀ (mg/kg) 14 >3,000 17 >3,000 28 >3,00039 >3,000 51 >3,000 57 >3,000

What is claimed is:
 1. A compound represented by the following formula(1):

In which R₁, R₃, and R₄ each independently represent hydrogen, halogen,hydroxy, alkyl, lower alkoxy, amino or nitro, R₂ represents

 wherein A represents amino which may be optionally substituted withalkyl, cycloalkyl, aralkyl, acyl, or aryl which is optionallysubstituted with one or two subsituents selected from the groupconsisting of halogen, cyano, nitro and amino; or1,2,3,4-tetrahydroisoquinoline which may be optionally substituted withhalogenoalkylcarbonyl; or alkyl, aryl, aralkyl or heteroaryl each ofwhich may be optionally substituted with one or two substituentsselected from the group consisting of alkyl, halogenoalkyl, halogen,dialkylamino, phenyl, nitro, amino,isooxazolyl, pyridine, carboxy,morpholine, methylpiperazine and cyano, Y represents SO₂, B representshydrogen or alkyl, R₅ represents hydrogen or hydroxy, and R₆ and R₇ aresubstituted at o-, m- or p-position from each other and eachindependently represents hydrogen, hydroxy, halogen or lower alkoxy ortogether represent lower alkylenedioxy, or a pharmaceutically acceptablesalt, hydrate, solvate and isomer thereof.
 2. The compound of claim 1,wherein R₁, R₃ and R₄ each independently represent hydrogen, halogen,hydroxy, alkyl or amino, provided that two or more of these threesubstituents are hydrogen, R₂ represents

 wherein A represents amino which may be optionally substituted withalkyl, cycloalkyl, aralkyl, acyl, or aryl which is optionallysubstituted with one or two substituents selected from the groupconsisting of halogen, cyano, nitro and amino; or1,2,3,4-tetrahydroisoquinoline which may be optionally substituted withhalogenoalkylcarbonyl; or alkyl, aryl, aralkyl or heteroaryl each ofwhich may by optionally substituted with one or two substituentsselected from the group consisting of alkyl, halogenoalkyl, halogen,dialkylamino, phenyl, nitro, amino, isooxazole, pyridine, carboxy,morpholine, methylpiperazinc and cyano, Y represents SO₂, B representshydrogen or alkyl, R₅ represents hydroxy, and R₆ and R₇ represent3-hydroxy and 4-hydroxy respectively.
 3. The compound of claim 2,wherein R₁, R₃ and R₄ each represent hydrogen, A represents amino whichmay be optionally substituted with cycloalkyl; or1,2,3,4-tetrahydroisoquinoline which may be optionally substituted withhalogenoalkylcarbonyl; or alkyl, aryl, aralkyl or heteroaryl each ofwhich may be optionally substituted with one or two substituentsselected from the group consisting of alkyl, halogenoalkyl, halogen,dialkylamino, phenyl, nitro, amino, isooxazole, pyridine, carboxy,morpholine and methylpiperazine, Y represents SO₂, and B representshydrogen.
 4. The compound of claim 3, wherein A represents1,2,3,4-tetrahydroisoquinoline which may be optionally substituted withhalogenoalkylcarbonyl; or aryl or heteroaryl each of which may beoptionally substituted with one or two substituents selected from thegroup consisting of alkyl, halogenoalkyl, halogen, dialkylamino, phenyl,nitro, amino, isooxazole, pyridine, carboxy, morpholine andmethylpiperazine.
 5. The compound of claim 1 which is selected from agroup consisting ofN-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-methylbenzencsulfonatnide,4-bromo-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]benzenesulfonamide,3-bromo-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]benzenesulfonamide,N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2-naphthalenesulfonamide,N-[2-(3,4-dihydroxyphonyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-5-(di-methylamino)-1-niphthalenesulfonamide,N-[2-(3,4-dihydroxyphonyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2-(1-naphthyl)-1-ethanesulfonamide,4,5-dibromo-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2-thiophenesulfonamide,N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-[-1,1′-biphenyl]-4-sulfonamide,N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-5-(iso-oxazolyl)-2-thiophenesulfonamide,N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-5-(2-pyridinyl)-2-thiophenesulfonamide,N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-chromen-6-yl]-3,4-di-fluorobenzenesulfonamide,N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]4-(tri-fluoromethyl)benzenesulfonamide,4-chloro-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-3-nitrobenzenesulfonamide,3-chloro-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-1-propanesulfonamide,N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-2,4-di-fluorobenzenesulfonamide,N-[2-(3,4-dihydroxyphonyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]4-fluorobenzenesulfonamide,N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4-H-chromen-6-yl]-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinesulfonamide,4-({(2-(3,4-dihydroxypbenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-amino}sulfonyl)benzoicacid,N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-1,2,3,4-tetrahydro-7-isoquinolinesulfonamnide,N-cyclohexyl-N′-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-sulfide,N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(4-morpholinyl)-3-nitrobenzenesulfonamide,N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamide, and3-amino-N-[2-(3,4-dihydroxyphenyl)-3-hydroxy-4-oxo-4H-chromen-6-yl]-4-(4-methyl-1-piperazinyl)benzenesulfonamide.6. A process for preparing the compound of formula (1) as defined inclaim 1, characterized in that a) a compound of formula (5):

 wherein R₁, R₂, R₃, R₄, R₆ and R₇ are defined as claim 1, is preparedby cyclizing a compound of formula (4):

 wherein R₁, R₂, R₃, R₄, R₆ and R₇ are defined as claim 1, in thepresence of trifluoroacetic acid, then thus obtained compound of formula(5) is oxidized in the presence of a oxidizing agent in a solvent toproduce a compound of formula (1a):

 wherein R₁, R₂, R₃, R₄, R₆ and R₇ are defined as claim 1; or b) acompound of formula (6):

 wherein R₁, R₂, R₃, R₄, R₆ and R₇ are defined as claim 1, is cyclizedin the presence of sodium acetate in a solvent to produce the compoundof formula (1a); or c) the compound of formula (4) is cyclized in thepresence of a base and hydrogen peroxide in a solvent to produce acompound of formula (1b)

 wherein R₁, R₂, R₃, R₄, R₆ and R₇ are defined as claim 1; or d) one tosix lower alkoxy groups or alkylenedioxy group in the compound offormula (1) are deprotected in the presence of boron tribromide (B3r₃)and converted into hydroxy or dihydroxy group to produce a compound offormula (1) wherein one to six of the sustainments R₁, R₂, R₃, R₄, R₆and R₇ are hydroxy; or c) a compound of formula (4a)

 wherein R₁, R₂, R₃, and R₄ are defined as claim 1, is prepared byreacting 2-hydroxyacetophenone derivative of formula (7):

 wherein R₁, R₂, R₃, and R₄ are defined as claim 1, with piperonal offormula (8a):

 in the presence of a base in a solvent, then thus obtained compound orformula (4a) is cyclized in the presence of hydroxy peroxide to producea compound of formula (1cc):

 wherein R₁, R₂, R₃ and R₄ are defined as claim 1; or f) the producedcompound or formula (1cc) is reacted with boron tribromide (BBr₃) toproduce a compound of formula a (1dd):

 wherein R₁, R₂, R₃ and R₄ are defined as claim 1; or g) a compound offormula (4b):

 wherein R₁, R₃, R₄ and B are defined as claim 1, is prepared byreacting 2-hydroxyacelophenone derivative of formula (7a):

 wherein R₁, R₃, R₄, and B are defined as claim 1, the piperonal offormula (8a), and sodium hydroxide in the aqueous ethanol solutionsolvent, then thus obtained compound of formula (4b) is reacted withaqueous sodium hydroxide and hydrogen peroxide in methanol solvent toproduce to a compound of formula (1e):

 wherein R₁, R₃, R₄ and B are defined in claim 1; or h) a compound offormula (9a):

 wherein R₁, R₁, R₄ and B are defined as claim 1, is prepared byhydrolyzing the produced compound of formula (1e) with aqueous sulfuricacid solution in alcoholic solvent, then thus obtained compound offormula (9a) is reacted with a compound of formula (10) A—Y—X  (10) wherein A and Y are defined as claim 1 and X is a leaving group toproduce a compound of formula (1hh):

 wherein R₁, R₃, R₄, A, Y and B are defined as claim 1; or i) theproduced compound of formula (1hh) is reacted with boron tribromide(BBr₃) in methylenechloride solvent to produce a compound of formula(1i):

 wherein R₁, R₃, R₄, A, Y and B are defined as claim
 1. 7. A compositionfor the treatment of cancer or neurodegenerative disease comprising thecompound of formula (1), pharmaceutically acceptable salt, hydrate,solvate or isomer thereof as defined in claim 1 as an active ingredientwith pharmaceutically acceptable carriers.